U.S. patent application number 17/632338 was filed with the patent office on 2022-09-08 for kif18a inhibitors.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Abhisek BANERJEE, Matthew Paul BOURBEAU, Nuria A. TAMAYO.
Application Number | 20220281843 17/632338 |
Document ID | / |
Family ID | 1000006407469 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220281843 |
Kind Code |
A1 |
TAMAYO; Nuria A. ; et
al. |
September 8, 2022 |
KIF18A INHIBITORS
Abstract
Compounds of formula (I): (I), as defined herein, and synthetic
intermediates thereof, which are capable of modulating KIF18A
protein thereby influencing the process of cell cycle and cell
proliferation to treat cancer and cancer-related diseases. The
invention also includes pharmaceutical compositions, including the
compounds, and methods of treating disease states related to the
activity of KIF18A. ##STR00001##
Inventors: |
TAMAYO; Nuria A.; (Newbury
Park, CA) ; BANERJEE; Abhisek; (Bangalore, Karnataka,
IN) ; BOURBEAU; Matthew Paul; (WOODLAND HILLS,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
THOUSAND OAKS |
CA |
US |
|
|
Assignee: |
AMGEN INC.
THOUSAND OAKS
CA
|
Family ID: |
1000006407469 |
Appl. No.: |
17/632338 |
Filed: |
August 3, 2020 |
PCT Filed: |
August 3, 2020 |
PCT NO: |
PCT/US2020/044800 |
371 Date: |
February 2, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62882271 |
Aug 2, 2019 |
|
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/14 20130101;
C07D 401/14 20130101; C07D 471/04 20130101; C07D 471/08 20130101;
C07D 413/14 20130101; C07D 401/04 20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 401/04 20060101 C07D401/04; C07D 413/14 20060101
C07D413/14; C07D 471/04 20060101 C07D471/04; C07D 405/14 20060101
C07D405/14; C07D 471/08 20060101 C07D471/08 |
Claims
1. A compound of formula I: ##STR00116## or any
pharmaceutically-acceptable salt thereof, wherein: X.sup.1 is N or
CR.sup.6; X.sup.2 is N or CR.sup.3a; X.sup.3 is N or CR.sup.3b;
X.sup.4 is N or CR.sup.3c; X.sup.5 is N or CR.sup.3d; X.sup.6 is N
or CR.sup.3e; X.sup.7 is N or CR.sup.3f; wherein no more than 3 of
X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are N; R.sup.1 is --CN, or a
group --Z--R.sup.8 wherein Z is --C.sub.0-4alk-, --NR.sup.7--,
--NR.sup.7SO.sub.2--, --SO.sub.2NR.sup.7--,
--N.dbd.S(.dbd.O)--(R.sup.7).sub.2 (wherein the two R.sup.7 pair
can alternatively combine with the sulfur atom attached to each of
them to form a saturated or partially-saturated 3-, 4-, 5-, or
6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0,
1, or 2 atoms selected from O and S),
--NR.sup.7--S(.dbd.O)(.dbd.NH), --S(.dbd.O)(.dbd.NH)--, --S--,
--S(.dbd.O)--, --SO.sub.2--, C.sub.0-4alk-O--, --(C.dbd.O)--,
--(C.dbd.O)NR.sup.7--, --C.dbd.N(OH)--, or --NR.sup.7(C.dbd.O);
R.sup.2 is halo or a group --Y--R.sup.9, wherein Y is
--C.sub.0-4alk-, --NR.sup.a--, --N(C.sub.1-4alk)-,
--NH--(CH.sub.2).sub.0-4--,
--C(.dbd.O)NR.sup.aR.sup.a(C.sub.1-4alk), --O--(CH.sub.2).sub.0-4,
C.sub.0-4alk-S--, C.sub.0-4alk-S.dbd.O,
C.sub.0-4alk-S(.dbd.O).sub.2, --SO.sub.2NR.sup.a--C.sub.0-4alk-,
--C.sub.0-4alk-S(.dbd.O)(.dbd.NH)--, --O--C.sub.0-4alk-,
--C.sub.0-4alk-(C.dbd.O)--, --C.sub.0-4alk-(C.dbd.O)--O--, or
--N.dbd.S(.dbd.O)<; L is --NW, --O--, --S--, S.dbd.O, or
S(.dbd.O).sub.2; R.sup.3 is H, C.sub.1-4alk, or C.sub.1-4haloalk;
R.sup.3a is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.3b is
H, halo, C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.3c is H, halo,
C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.3d is H, halo,
C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.3e is H, halo,
C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.3f is H, halo,
C.sub.1-8alk, or C.sub.1-4haloalk; R.sup.4 is H, halo, R.sup.4a or
R.sup.4b; R.sup.5 is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
R.sup.6 is H, halo, C.sub.1-8alk, C.sub.1-4haloalk,
--O--C.sub.1-8alk, or --O--R.sup.6a; wherein R.sup.6a is a
saturated or partially-saturated 3-, 4-, 5-, or 6-membered
monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2
atoms selected from O and S; R.sup.X is selected from H,
##STR00117## Each of R.sup.Xa, R.sup.Xb, R.sup.Xc, R.sup.Xd,
R.sup.Xe, R.sup.Xf, R.sup.Xg, R.sup.Xh, R.sup.Xi, R.sup.Xj,
R.sup.Xk, and R.sup.Xl is H, halo, R.sup.Xm, or R.sup.Xn; or
alternatively, each of R.sup.Xa and R.sup.Xb pair, R.sup.Xc and
R.sup.Xd pair, R.sup.Xe and R.sup.Xf pair, R.sup.Xg and R.sup.Xh
pair, R.sup.Xi and R.sup.Xj pair, and R.sup.Xk and R.sup.Xl pair,
independently, can combine with the carbon atom attached to each of
them to form a saturated or partially-saturated 3-, 4-, 5-,
6-membered monocyclic ring spiro to the azetidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, or azepanyl ring; wherein said 3-, 4-,
5-, 6-membered monocyclic ring contains 0 N, O, and S atoms, and
further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --NR.sup.aR.sup.a, or oxo; R.sup.7 is H, R.sup.7a, or R.sup.7b;
R.sup.8 is H, R.sup.8a, or R.sup.8b; R.sup.9 is R.sup.9a or
R.sup.9b; R.sup.4a, R.sup.Xm, R.sup.7a, R.sup.8a, and R.sup.9a is
independently, at each instance, selected from the group consisting
of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-,
or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-11-, or
12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1,
or 2 atoms selected from O and S, which is substituted by 0, 1, 2
or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkOR.sup.a, --C.sub.1-6alkN(R.sup.a)C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a, R.sup.10, and oxo; R.sup.4b,
R.sup.Xn, R.sup.8b, R.sup.8b, and R.sup.9b is independently, at
each instance, selected from the group consisting of C.sub.1-6alk
substituted by 0, 1, 2, 3, 4, or 5 group(s) selected from F, Cl,
Br, --OR.sup.a, --OC.sub.1-4haloalk, or CN; R.sup.10 is
independently, at each instance, selected from the group consisting
of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-,
or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or
1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3
group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OR.sup.a, --OC.sub.1-4haloalk, CN, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkOR.sup.a, --C.sub.1-6alkN(R.sup.a)C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a, and oxo; R.sup.a is independently,
at each instance, H or R.sup.b; and R.sup.b is independently, at
each instance, C.sub.1-6alk, phenyl, or benzyl, wherein the
C.sub.1-6alk is being substituted by 0, 1, 2 or 3 substituents
selected from halo, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk; and the phenyl or benzyl is being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, --OC(.dbd.O)C.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk.
2. The compound according to claim 1, wherein X.sup.1 is CR.sup.6;
X.sup.2 is CR.sup.3a; X.sup.3 is N; X.sup.4 is CR.sup.3c; X.sup.5
is N; X.sup.6 is CR.sup.3e; and X.sup.7 is CR.sup.3f; having the
formula (Ia): ##STR00118## wherein said R.sup.Xa and R.sup.Xb pair
can combine with the carbon atom attached to each of them to form a
saturated or partially-saturated 3-, 4-, 5-, 6-membered monocyclic
ring Spiro to the piperidinyl ring; wherein said 3-, 4-, 5-,
6-membered monocyclic ring contains 0 N, O, and S atoms, and
further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --NR.sup.aR.sup.a, or oxo.
3. The compound according to claim 1, wherein X.sup.1 is N; X.sup.2
is CR.sup.3a; X.sup.3 is N; X.sup.4 is CR.sup.3c; X.sup.5 is N;
X.sup.6 is CR.sup.3e; and X.sup.7 is CR.sup.3f; having the formula
(Ib): ##STR00119## wherein said R.sup.Xa and R.sup.Xb pair can
combine with the carbon atom attached to each of them to form a
saturated or partially-saturated 3-, 4-, 5-, 6-membered monocyclic
ring spiro to the piperidinyl ring; wherein said 3-, 4-, 5-,
6-membered monocyclic ring contains 0 N, O, and S atoms, and
further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --NR.sup.aR.sup.a, or oxo.
4. The compound according to claim 1, wherein X.sup.1 is CR.sup.6;
X.sup.2 is N; X.sup.3 is N; X.sup.4 is CR.sup.3c; X.sup.5 is N;
X.sup.6 is CR.sup.3e; and X.sup.7 is CR.sup.3f; having the formula
(Ic): ##STR00120## wherein said R.sup.Xa and R.sup.Xb pair can
combine with the carbon atom attached to each of them to form a
saturated or partially-saturated 3-, 4-, 5-, 6-membered monocyclic
ring Spiro to the piperidinyl ring; wherein said 3-, 4-, 5-,
6-membered monocyclic ring contains 0 N, O, and S atoms, and
further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --NR.sup.aR.sup.a, or oxo.
5. The compound according to claim 1, wherein X.sup.1 is N; X.sup.2
is N; X.sup.3 is N; X.sup.4 is CR.sup.3c; X.sup.5 is N; X.sup.6 is
CR.sup.3e; and X.sup.7 is CR.sup.3f; having the formula (Id):
##STR00121## wherein said R.sup.Xa and R.sup.Xb pair can combine
with the carbon atom attached to each of them to form a saturated
or partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro
to the piperidinyl ring; wherein said 3-, 4-, 5-, 6-membered
monocyclic ring contains 0 N, O, and S atoms, and further wherein
said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1,
2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--NR.sup.aR.sup.a, or oxo.
6. The compound according to claim 1, wherein X.sup.1 is CR.sup.6;
X.sup.2 is CR.sup.3a; X.sup.3 is N; X.sup.4 is N; X.sup.5 is
CR.sup.3d; X.sup.6 is CR.sup.3e; and X.sup.7 is CR.sup.3f; having
the formula (Ie): ##STR00122## wherein said R.sup.Xa and R.sup.Xb
pair can combine with the carbon atom attached to each of them to
form a saturated or partially-saturated 3-, 4-, 5-, 6-membered
monocyclic ring spiro to the piperidinyl ring; wherein said 3-, 4-,
5-, 6-membered monocyclic ring contains 0 N, O, and S atoms, and
further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --NR.sup.aR.sup.a, or oxo.
7. The compound according to claim 1, wherein R.sup.3 is H or
methyl.
8. The compound according to claim 1, wherein each of R.sup.Xc,
R.sup.Xd, R.sup.Xe, R.sup.Xf, R.sup.Xg, R.sup.Xh, R.sup.Xi,
R.sup.Xj, R.sup.Xk, and R.sup.Xl is H, halo, C.sub.1-6alk, or
C.sub.1-4haloalk; and each of R.sup.Xa and R.sup.Xb pair combine
with the carbon atom attached to each of them form a saturated 3-,
4-, or 5-membered monocyclic ring spiro to the piperidinyl ring;
wherein said ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atoms
selected from O and S.
9. The compound according to claim 1, wherein each of R.sup.Xc,
R.sup.Xd, R.sup.Xe, R.sup.Xf, R.sup.Xg, R.sup.Xh, R.sup.Xi,
R.sup.Xj, R.sup.Xk, and R.sup.Xl is H, methyl, or ethyl; and each
of R.sup.Xa and R.sup.Xb pair combine with the carbon atom attached
to each of them form a cyclopropyl, cyclobutyl, or cyclopentyl ring
spiro to the piperidinyl ring.
10. The compound according to claim 1, wherein the group
##STR00123## is selected from: ##STR00124##
11. The compound according to claim 1, wherein the group is
##STR00125##
12. The compound according to claim 1, wherein R.sup.1 is --CN, or
a group --Z--R.sup.8, wherein Z is absent, --NH--, --NHSO.sub.2--,
--SO.sub.2NH--, --N.dbd.S(.dbd.O)--(R.sup.11).sub.2 (wherein the
two R.sup.7 pair can alternatively combine with the sulfur atom
attached to each of them to form a saturated or partially-saturated
3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N
atoms and 0, 1, or 2 atoms selected from O and S),
--S(.dbd.O)(.dbd.NH)--, --S--, --S(.dbd.O)--, --SO.sub.2--,
--(C.dbd.O)--, --(C.dbd.O)NH--, or --NH(C.dbd.O)--; and R.sup.8 is
selected from: (a) H; (b) cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl,
imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, ##STR00126##
wherein each said ring is substituted by 0, 1, 2 or 3 group(s)
selected from wherein each ring is substituted by 0, 1, 2 or 3 OH,
F, methyl, --CH.sub.2OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)OC(CH.sub.3).sub.3, NH.sub.2, CN, and oxo; or (c)
C.sub.1-6alk substituted by 0, 1, 2 or 3 OH, F,
--C(.dbd.O)OCH.sub.3, --NH.sub.2, --NH(CH.sub.3), or
--N(CH.sub.3).sub.2.
13. The compound according to claim 1, wherein R.sup.1 is --CN, or
a group --Z--R.sup.8, wherein Z is absent, --NH--, --NHSO.sub.2--,
--SO.sub.2NH--, --N.dbd.S(.dbd.O)--(R.sup.7).sub.2 (wherein the two
R.sup.7 pair can alternatively combine with the sulfur atom
attached to each of them to form a saturated or partially-saturated
3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N
atoms and 0, 1, or 2 atoms selected from O and S),
--S(.dbd.O)(.dbd.NH)--, --S--, --S(.dbd.O)--, --SO.sub.2--,
--(C.dbd.O)--, --(C.dbd.O)NH--, or --NH(C.dbd.O)--; and (c) R.sup.8
is H; (d) R.sup.8 is oxetanyl, cyclopropyl; or (e) R.sup.8 is
C.sub.1-6alk substituted by 0, 1, 2 or 3 OH group(s).
14. The compound according to claim 1, wherein R.sup.1 is a group
--Z--R.sup.8, wherein Z is --N.dbd.S(.dbd.O)--(R.sup.7).sub.2;
wherein each R.sup.7 is independently selected from the group
consisting of H, methyl, or isopropyl; or the two R.sup.7 pair can
alternatively combine with the sulfur atom attached to each of them
to form a saturated or partially-saturated 3-, 4-, 5-, or
6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0,
1, or 2 atoms selected from O and S, which is selected from:
##STR00127##
15. The compound according to claim 1, wherein R.sup.1 is a group
--Z--R.sup.8, wherein Z is --SO.sub.2; --NHSO.sub.2--;
--SO.sub.2NH--; or --S(.dbd.O)(.dbd.NH)--; and R.sup.8 is H,
oxetanyl, cyclopropyl, or R.sup.8 is C.sub.1-6alk substituted by 0,
1, 2 or 3 OH group(s).
16. The compound according to claim 1, wherein R.sup.1 is a group
--Z--R.sup.8, wherein Z is --NHSO.sub.2-- and R.sup.8 is
--CH.sub.2--CH.sub.2--OH.
17. The compound according to claim 1, wherein R.sup.1 is a group
--Z--R.sup.8, wherein Z is --SO.sub.2; and R.sup.8 is methyl.
18. The compound according to claim 1, wherein R.sup.1 is a group
--Z--R.sup.8, wherein Z is --S(.dbd.O)(.dbd.NH)--; and R.sup.8 is
cyclopropyl.
19. The compound according to claim 1, wherein R.sup.1 is H.
20. The compound according to claim 1, wherein R.sup.2 is halo or a
group --Y--R.sup.9, wherein Y is absent, --NH--,
--NH--(CH.sub.2).sub.0-4--, or --O--(CH.sub.2).sub.0-4; and R.sup.9
is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-,
or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or
1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3
group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OH, --OC.sub.1-4haloalk, CN, R.sup.10, and oxo; or R.sup.9 is
C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s) selected
from F, Cl, Br, --OH, --OC.sub.1-4haloalk, or CN.
21. The compound according to claim 1, wherein R.sup.2 is a
saturated 5- or 6-membered monocyclic ring wherein each said ring
contains 0, 1, or 2 N atoms and 0 or 1 O atom, and wherein each
said ring is substituted by 0, 1, 2 or 3 group(s) selected from F,
Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk, --OH, --OC.sub.1-4haloalk,
CN, R.sup.10, and oxo.
22. The compound according to claim 1, wherein R.sup.2 is (a) halo;
(b) a group --Y--R.sup.9, wherein Y is absent; and R.sup.9 is
morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl,
tetrahydrofuranyl, ##STR00128## ##STR00129## wherein each said ring
is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
methyl, CF.sub.3, --OH, --OCHF.sub.2, CN, and oxo; or (c) a group
--Y--R.sup.9, wherein Y is NH, --O--, --O--(CH.sub.2)--,
--O--(CH.sub.2)--(CH.sub.2)--, or
--O--(CH.sub.2)--(CH.sub.2)--(CH.sub.2)--, and wherein R.sup.9 is
##STR00130## or R.sup.9 is C.sub.1-6alk substituted by 0, 1, 2, 3,
4, or 5 group(s) selected from F, Cl, Br, methyl, CF.sub.3, --OH,
or CN.
23. The compound according to claim 1, wherein R.sup.2 is
morpholinyl or piperidinyl substituted by 0, 1, 2 or 3 group(s)
selected from F, Cl, Br, methyl, CF.sub.3, --OH, --OCHF.sub.2, CN,
or oxo.
24. The compound according to claim 1, wherein R.sup.2 is
morpholinyl substituted by 1, 2 or 3 methyl group(s).
25. The compound according to claim 1, wherein R.sup.2 is
piperidinyl substituted by 1, 2 or 3 fluoro group(s).
26. The compound according to claim 1, wherein R.sup.2 is
##STR00131##
27. The compound according to claim 1, wherein R.sup.2 is methyl or
--O--(CH.sub.2)--(CH.sub.2)--CF.sub.3.
28. The compound according to claim 1, wherein Z is absent, --NH--,
--NHSO.sub.2--, --SO.sub.2NH--,
--N.dbd.S(.dbd.O)<(R.sup.a).sub.2 (wherein each R.sup.7 is
independently selected from the group consisting of H, methyl, or
isopropyl), --S(.dbd.O)(.dbd.NH)--, --S--, --S(.dbd.O)--,
--SO.sub.2--, --(C.dbd.O)--, --(C.dbd.O)NH--, or
--NH(C.dbd.O)--.
29. The compound according to claim 1, wherein R.sup.8 is selected
from (a) H; (b) C.sub.1-6alk substituted by 0, 1, 2 or 3 group(s)
selected from F, Cl, Br, --OH, --OCH.sub.3, or cyclopropyl; or (c)
a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or
7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or
1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3
group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--C.sub.1-6alkOH, --OH, --OCH.sub.3, --NH.sub.2, or oxo.
30. The compound according to claim 1, wherein R.sup.8 is selected
from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, or 1,3,4-oxathiazinanyl.
31. The compound according to claim 1, wherein R.sup.3 is H.
32. The compound according to claim 1, wherein R.sup.4 is selected
from (a) H; (b) C.sub.1-6alk substituted by 0, 1, 2 or 3 OH
group(s); or (c) cyclopropyl.
33. The compound according to claim 1, wherein R.sup.4 is
methyl.
34. The compound according to claim 1, wherein R.sup.5 is H.
35. The compound according to claim 1, wherein R.sup.6 is H or
F.
36. The compound according to claim 1, wherein R.sup.3a is H or
F.
37. The compound according to claim 1, wherein R.sup.3b is H.
38. The compound according to claim 1, wherein R.sup.3c is H.
39. The compound according to claim 1, wherein R.sup.3d is H.
40. The compound according to claim 1, wherein R.sup.3e is H.
41. The compound according to claim 1, wherein R.sup.3f is H.
42. The compound according to claim 1, or any
pharmaceutically-acceptable salt thereof, selected from the group
consisting of:
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-2-methyl-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfonyl)-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-4-amine;
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-
-6-yl)quinazolin-4-amine;
(R)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone;
(S)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone;
2-Hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
N-(4-((3,5-Dimethylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin--
7-yl)-2-hydroxyethane-1-sulfonamide;
N-(5-(6-Azaspiro[2.5]octan-6-yl)-4-((3-(3,3,3-trifluoropropoxy)phenyl)ami-
no)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6--
azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenoxy)-5-(6-azaspiro[2.5]o-
ctan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(1-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro-
[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide;
(R)-2-Hydroxy-N-(4-((3-methyl-5-(2-methylmorpholino)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
(R)-2-Hydroxy-N-(4-((4-methyl-6-(2-methylmorpholino)pyridin-2-yl)amino)-5-
-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
(R)-2-Hydroxy-N-(4-((6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)amino)-
-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
2-Hydroxy-N-(4-((2-((1-hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimid-
in-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfo-
namide;
N-(4-((2-Fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)ami-
no)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfon-
amide;
2-Hydroxy-N-(4-((3-(2-hydroxy-2-methylpropoxy)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-N-(3-met-
hyloxetan-3-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide;
(S)-N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(-
6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-1-hydroxypropane-2-sulfonamide;
(R)-N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(-
6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-1-hydroxypropane-2-sulfonamide;
N-(4-((2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-a-
zaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-8-flu-
oro-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfon-
amide;
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-
-5-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-2-hydroxyethane-
-1-sulfonamide;
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(7--
azaspiro[3.5]nonan-7-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(4-((2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-5-(4,4-dimethy-
lazepan-1-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
2-((4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)sulfonyl)ethan-1-ol;
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)thio)-5-(6-azaspiro[-
2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
7-(Azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrim-
idin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine;
N-(tert-Butyl)-3-((7-((2-hydroxyethyl)sulfonamido)-5-(6-azaspiro[2.5]octa-
n-6-yl)quinazolin-4-yl)amino)benzenesulfonamide;
N-(4-((3-(Cyclopentylsulfonyl)-4-methylphenyl)amino)-5-(6-azaspiro[2.5]oc-
tan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
N-(tert-Butyl)-4-((6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide;
N-(tert-Butyl)-4-(chroman-5-ylamino)-5-(6-azaspiro[2.5]octan-6-yl)quinazo-
line-7-sulfonamide;
N-(1-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-8-(6-az-
aspiro[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide;
N-(1-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-8-(6-az-
aspiro[2.5]octan-6-yl)isoquinolin-6-yl)-2-hydroxyethane-1-sulfonamide;
N-(1-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro-
[2.5]octan-6-yl)isoquinolin-6-yl)-2-hydroxyethane-1-sulfonamide;
2-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)isothiazolidine 1,1-dioxide;
N-(4-((3-(3,3-Difluoro-6-azabicyclo[3.1.1]heptan-6-yl)-5-methylphenyl)ami-
no)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfon-
amide;
N-(4-((3-(6,6-Difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-5-methylphen-
yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1--
sulfonamide;
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-4-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-N-(2-hydroxyethy-
l)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-carboxamide;
2-((8-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-1-(6-azaspir-
o[2.5]octan-6-yl)-2,7-naphthyridin-3-yl)amino)-2-methylpropan-1-ol;
2-((5-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-4-(6-azaspir-
o[2.5]octan-6-yl)-1,6-naphthyridin-2-yl)amino)-2-methylpropan-1-ol;
2-((5-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-4-(6-azaspir-
o[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)amino)-2-methylpropan-1-ol;
2-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)propan-2-ol; or
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-
-6-yl)pyrido[3,4-d]pyrimidin-4-amine.
43. The compound of claim 1, selected from the group consisting of:
TABLE-US-00010 Exam- ple # Chemical Structure Name 100 ##STR00132##
N-(4-((3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)amino)-5-
(6-azaspiro[2.5]octan-6-yl) quinazolin-7-yl)-2-hydroxy-
ethane-1-sulfonamide 100-1 ##STR00133##
N-(4-((3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)amino)-2-
methyl-5-(6-azaspiro[2.5]octan- 6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 101 ##STR00134##
N-(3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)-7-
(methylsulfonyl)-5-(6-azaspiro [2.5]octan-6-yl)quinazolin-4- amine
101-1 ##STR00135## N-(3-(4,4-Difluoropiperidin-
1-yl)-5-methylphenyl)-5-(6- azaspiro[2.5]octan-6-yl)
quinazolin-4-amine 102-1 ##STR00136## (R)-Cyclopropyl(4-((3-(4,4-
difluoropiperidin-1-yl)-5- methylphenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl) quinazolin-7-yl)(imino)-16- sulfanone
102-2 ##STR00137## (S)-Cyclopropyl(4-((3-(4,4-
difluoropiperidin-1-yl)-5- methylphenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl) quinazolin-7-yl)(imino)-16- sulfanone 103
##STR00138## 2-Hydroxy-N-(4-((3-methyl- 5-(3,3,3-trifluoropropoxy)
phenyl)amino)-5-(6-azaspiro [2.5]octan-6-yl)quinazolin-7-
yl)ethane-1-sulfonamide 103-1 ##STR00139##
N-(4-((3,5-Dimethylphenyl) amino)-5-(6-azaspiro[2.5]octan-
6-yl)quinazolin-7-yl)-2- hydroxyethane-1-sulfonamide 103-2
##STR00140## N-(5-(6-Azaspiro[2.5]octan-6- yl)-4-((3-(3,3,3-
trifluoropropoxy)phenyl)amino) quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 104 ##STR00141##
N-(4-((2-(4,4-Difluoro- piperidin-1-yl)-6- methylpyrimidin-4-yl)
amino)-5-(6-azaspiro[2.5] octan-6-yl)quinazolin-7-yl)-
2-hydroxyethane-1- sulfonamide 105 ##STR00142##
N-(4-((2-(4,4-Difluoropiperidin- 1-yl)-6-methylpyridin-4-yl)
amino)-5-(6-azaspiro[2.5]octan- 6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 105-1 ##STR00143##
N-(4-((6-(4,4-Difluoropiperidin- 1-yl)-4-methylpyridin-2-yl)
amino)-5-(6-azaspiro[2.5]octan- 6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 105-2 ##STR00144##
N-(4-(3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenoxy)-5-(6-
azaspiro[2.5]octan-6-yl) quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 106 ##STR00145##
N-(1-((3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)amino)-8-
(6-azaspiro[2.5]octan-6-yl) phthalazin-6-yl)-2-hydroxy-
ethane-1-sulfonamide;
or any pharmaceutically-acceptable salt thereof.
44. A pharmaceutical composition comprising the compound according
to claim 1 or the pharmaceutically acceptable salt thereof, and a
pharmaceutically-acceptable diluent or carrier.
45. A method of treating a condition that may be treated with
KIF18a inhibitors, the method comprising administering to a patient
in need thereof a therapeutically effective amount of the compound
in accordance with claim 1, wherein said condition is cancer
selected from the group consisting of (a) a solid or
hematologically derived tumor selected from cancer of the cancer of
the bladder, endometrial, lung squamous cell, breast, colon,
kidney, liver, lung, small cell lung cancer, esophagus,
gall-bladder, brain, head and neck, ovary, pancreas, stomach,
cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of
lymphoid lineage selected from leukemia, acute lymphocitic
leukemia, acute lymphoblastic leukemia, B-cell lymphoma,
T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy
cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of
myeloid lineage selected from acute and chronic myelogenous
leukemias, myelodysplastic syndrome and promyelocytic leukemia (d)
a tumor of mesenchymal origin selected from fibrosarcoma and
rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous
system selected from astrocytoma, neuroblastoma, glioma and
schwannoma, or (f) a melanoma, seminoma, teratocarcinoma,
osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid
follicular cancer or Kaposi's sarcoma.
46. (canceled)
47. A method of reducing the size of a solid tumor in a subject,
the method comprising administering to the subject in need thereof
a therapeutically effective amount of the compound in accordance
with claim 1.
48. A method of treating a cell proliferation disorder in a
subject, the method comprising administering to the subject in need
thereof a therapeutically effective amount of the compound in
accordance with claim 1.
49. A method of inhibiting KIF18A in a cell, comprising contacting
the cell with a compound, or pharmaceutically acceptable salts
thereof, in accordance with claim 1.
Description
[0001] The invention relates to the field of pharmaceutical agents
and, more specifically, is directed to compounds and compositions
useful for modulating KIF18A, and to uses and methods for managing
cell proliferation and for treating cancer.
BACKGROUND OF THE INVENTION
[0002] Cancer is one of the most widespread diseases afflicting
mankind and a major cause of death worldwide. In an effort to find
an effective treatment or a cure for one or more of the many
different cancers, over the last couple of decades, numerous groups
have invested a tremendous amount of time, effort and financial
resources. However, to date, of the available cancer treatments and
therapies, only a few offer any considerable degree of success.
[0003] Cancer is often characterized by unregulated cell
proliferation. Damage to one or more genes, responsible for the
cellular pathways, which control progress of proliferation through
the cell cycle and centrosome cycle, can cause the loss of normal
regulation of cell proliferation. These deregulated genes can code
for various tumor suppressor or oncogene proteins, which
participate in a cascade of events, leading to unchecked
cell-cycling progression and cell proliferation. Various kinase and
kinesin proteins have been identified, which play key roles in cell
cycle and mitotic regulation and progression of normal dividing
cells and cancer cells.
[0004] Kinesins are molecular motors that play important roles in
cell division and intracellular vesicle and organelle transport.
Mitotic kinesin play roles in several aspects of spindle assembly,
chromosome segregation, centrosome separation and dynamics
(reviewed in O. Rath and F. Kozielski, Nature Review Cancer,
12:527-39, 2012). Human kinesins are categorized into 14
subfamilies based on sequence homology within the so-called "motor
domain", this domains ATPase activity drives unidirectional
movement along microtubules (MTs). The non-motor domain of these
proteins is responsible for cargo attachment; a "cargo" can include
any one of a variety of different membranous organelles, signal
transduction scaffolding systems, and chromosomes. Kinesins use the
energy of ATP hydrolysis to move cargo along polarized
microtubules. Thus, kinesins are often called "plus-end" or
"minus-end" directed motors.
[0005] KIF18A gene belongs to Kinesin-8 subfamily and is a
plus-end-directed motor. KIF18A is believed to influence dynamics
at the plus end of kinetochore microtubules to control correct
chromosome positioning and spindle tension. Depletion of human
KIF18A leads to longer spindles, increased chromosome oscillation
at metaphase, and activation of the mitotic spindle assembly
checkpoint in HeLa cervical cancer cells (MI Mayr et al, Current
Biology 17, 488-98, 2007). KIF18A appears to be viable target for
the treatment of cancer. KIF18A is overexpressed in various types
of cancers, including but not limited to colon, breast, lung,
pancreas, prostate, bladder, head, neck, cervix, and ovarian
cancers. Further, genetic deletion or knockdown, or inhibition of
KIF18A effects mitotic spindle apparatus in cancer cell lines.
Particularly, inhibition of KIF18A has been found to induce mitotic
cell arrest, a known vulnerability that can promote cell death in
mitosis via apoptosis, mitotic catastrophe, or multipolarity driven
lethality or death after mitotic slippage in interphase.
Accordingly, there has been a strong interest in finding inhibitors
of KIF18A proteins.
[0006] Thus, the inhibition of KIF18A ATPase activity is a
promising approach for the development of novel anti-cancer
agents.
SUMMARY OF THE INVENTION
[0007] An aspect of the present invention is a new class of
compounds useful for modulating KIF18A protein alone or in a bound
complex with microtubules for treating KIF18A-mediated conditions
and/or diseases, including cancer, inflammation, or
ciliopathologies.
[0008] The compounds provided by the invention have MT-based KIF18A
modulatory activity and, in particular, KIF18A inhibitory activity.
To this end, the invention also provides the use of these
compounds, as well as pharmaceutically acceptable salts thereof, in
the preparation and manufacture of a pharmaceutical composition or
medicament for therapeutic, prophylactic, acute or chronic
treatment of KIF18A mediated diseases and disorders, including
without limitation, cancer. Thus, the compounds of the invention
are useful in the manufacture of anti-cancer medicaments. The
invention also provides processes for making compounds of Formula
I, as well as intermediates useful in such processes.
[0009] In embodiment 1, the present invention provides a compound
of Formula (I), A compound of formula I:
##STR00002##
[0010] or any pharmaceutically-acceptable salt thereof,
wherein:
[0011] X.sup.1 is N or CR.sup.6;
[0012] X.sup.2 is N or CR.sup.3a;
[0013] X.sup.3 is N or CR.sup.3b;
[0014] X.sup.4 is N or CR.sup.3c;
[0015] X.sup.5 is N or CR.sup.3d;
[0016] X.sup.6 is N or CR.sup.3e;
[0017] X.sup.7 is N or CR.sup.3f;
[0018] wherein no more than 3 of X.sup.3, X.sup.4, X.sup.5 and
X.sup.6 are N;
[0019] R.sup.1 is --CN, or a group --Z--R.sup.8 wherein Z is
--C.sub.0-4alk-, --NR.sup.7--, --NR.sup.7SO.sub.2--,
--SO.sub.2NR.sup.7--, --N.dbd.S(.dbd.O)--(R.sup.7).sub.2 (wherein
the two R.sup.7 pair can alternatively combine with the sulfur atom
attached to each of them to form a saturated or partially-saturated
3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2 or 3 N
atoms and 0, 1, or 2 atoms selected from O and S),
--NR.sup.7--S(.dbd.O)(.dbd.NH), --S(.dbd.O)(.dbd.NH)--, --S--,
--S(.dbd.O)--, --SO.sub.2--, C.sub.0-4alk-O--, --(C.dbd.O)--,
--(C.dbd.O)NR.sup.7--, --C.dbd.N(OH)--, or --NR.sup.7(C.dbd.O);
[0020] R.sup.2 is halo or a group --Y--R.sup.9, wherein Y is
--C.sub.0-4alk-, --NR.sup.a--, --N(C.sub.1-4alk)-,
--NH--(CH.sub.2).sub.0-4--,
--C(.dbd.O)NR.sup.aR.sup.a(C.sub.1-4alk), --O--(CH.sub.2).sub.0-4,
C.sub.0-4alk-S--, C.sub.0-4alk-S.dbd.O,
C.sub.0-4alk-S(.dbd.O).sub.2, --SO.sub.2NR.sup.a--C.sub.0-4alk-,
--C.sub.0-4alk-S(.dbd.O)(.dbd.NH)--, --O--C.sub.0-4alk-,
--C.sub.0-4alk-(C.dbd.O)--, --C.sub.0-4alk-(C.dbd.O)--O--, or
--N.dbd.S(.dbd.O)<;
[0021] L is --NW, --O--, --S--, S.dbd.O, or S(.dbd.O).sub.2;
[0022] R.sup.3 is H, C.sub.1-4alk, or C.sub.1-4haloalk;
[0023] R.sup.3a is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0024] R.sup.3b is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0025] R.sup.3c is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0026] R.sup.3d is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0027] R.sup.3e is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0028] R.sup.3f is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0029] R.sup.4 is H, halo, R.sup.4a or R.sup.4b;
[0030] R.sup.5 is H, halo, C.sub.1-8alk, or C.sub.1-4haloalk;
[0031] R.sup.6 is H, halo, C.sub.1-8alk, C.sub.1-4haloalk,
--O--C.sub.1-8alk, or --O--R.sup.6a; wherein R.sup.6a is a
saturated or partially-saturated 3-, 4-, 5-, or 6-membered
monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1, or 2
atoms selected from O and S;
[0032] R.sup.X is selected from H,
##STR00003##
[0033] Each of R.sup.Xa, R.sup.Xb, R.sup.Xc, R.sup.Xd, R.sup.Xe,
R.sup.Xf, R.sup.Xg, R.sup.Xh, R.sup.Xi, R.sup.Xj, R.sup.Xk and
R.sup.Xl is H, halo, R.sup.Xm, or R.sup.Xn;
[0034] or alternatively, each of R.sup.Xa and R.sup.Xb pair,
R.sup.Xc and R.sup.Xd pair, R.sup.Xe and R.sup.Xf pair, R.sup.Xg
and R.sup.Xh pair, R.sup.Xi and R.sup.Xj pair, and R.sup.Xk and
R.sup.Xl pair, independently, can combine with the carbon atom
attached to each of them to form a saturated or partially-saturated
3-, 4-, 5-, 6-membered monocyclic ring spiro to the azetidinyl,
pyrrolidinyl, piperidinyl, morpholinyl, or azepanyl ring; wherein
said 3-, 4-, 5-, 6-membered monocyclic ring contains 0 N, O, and S
atoms, and further wherein said 3-, 4-, 5-, 6-membered monocyclic
ring is substituted by 0, 1, 2 or 3 group(s) selected from F, Cl,
Br, C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a,
--OC.sub.1-4haloalk, CN, --NR.sup.aR.sup.a, or oxo;
[0035] R.sup.7 is H, R.sup.7a, or R.sup.7b;
[0036] R.sup.8 is H, R.sup.8a, or R.sup.9b;
[0037] R.sup.9 is R.sup.9a or R.sup.9b;
[0038] R.sup.4a, R.sup.Xm, R.sup.7a, R.sup.8a, and R.sup.9a is
independently, at each instance, selected from the group consisting
of a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-,
or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1,
or 2 atoms selected from O and S, which is substituted by 0, 1, 2
or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.b,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkO.sup.a, --C.sub.1-6alkN(R.sup.a)C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a, R.sup.10, and oxo;
[0039] R.sup.4b, R.sup.Xn, R.sup.8b, R.sup.8b, and R.sup.9b is
independently, at each instance, selected from the group consisting
of C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5 group(s)
selected from F, Cl, Br, --OR.sup.a, --OC.sub.1-4haloalk, or
CN;
[0040] R.sup.10 is independently, at each instance, selected from
the group consisting of a saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-,
7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1,
2 or 3 N atoms and 0 or 1 atoms selected from O and S, which is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk,
CN, --C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a, --C.sub.1-6alkNR.sup.aR.sup.a,
--C.sub.1-6alkOR.sup.a, --C.sub.1-6 alkN(R.sup.a)C(.dbd.O)R.sup.b,
--C.sub.1-6alkOC(.dbd.O)R.sup.b,
--C.sub.1-6alkC(.dbd.O)NR.sup.aR.sup.a,
--C.sub.1-6alkC(.dbd.O)OR.sup.a, and oxo;
[0041] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0042] R.sup.b is independently, at each instance, C.sub.1-6alk,
phenyl, or benzyl, wherein the C.sub.1-6alk is being substituted by
0, 1, 2 or 3 substituents selected from halo, --OH,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk,
--OC(.dbd.O)C.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk; and the
phenyl or benzyl is being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk, --OH,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk,
--OC(.dbd.O)C.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk.
[0043] In embodiment 2, the present invention provides compounds
wherein X.sup.1 is CR.sup.6; X.sup.2 is CR.sup.3a; X.sup.3 is N;
X.sup.4 is CR.sup.3c; X.sup.5 is N; X.sup.6 is CR.sup.3e; and
X.sup.7 is CR.sup.3f; having the formula (Ia):
##STR00004##
wherein said R.sup.Xa and R.sup.Xb pair can combine with the carbon
atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to
the piperidinyl ring; wherein said 3-, 4-, 5-, 6-membered
monocyclic ring contains 0 N, O, and S atoms, and further wherein
said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1,
2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--NR.sup.aR.sup.a, or oxo.
[0044] In embodiment 3, the present invention provides compounds
wherein X.sup.1 is N; X.sup.2 is CR.sup.3a; X.sup.3 is N; X.sup.4
is CR.sup.3c; X.sup.5 is N; X.sup.6 is CR.sup.3e; and X.sup.7 is
CR.sup.3f; having the formula (Ib):
##STR00005##
wherein said R.sup.Xa and R.sup.Xb pair can combine with the carbon
atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to
the piperidinyl ring; wherein said 3-, 4-, 5-, 6-membered
monocyclic ring contains 0 N, O, and S atoms, and further wherein
said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1,
2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--NR.sup.aR.sup.a, or oxo.
[0045] In embodiment 4, the present invention provides compounds
wherein X.sup.1 is CR.sup.6; X.sup.2 is N; X.sup.3 is N; X.sup.4 is
CR.sup.3c; X.sup.5 is N; X.sup.6 is CR.sup.3e; and X.sup.7 is
CR.sup.3f; having the formula (Ic):
##STR00006##
Wherein said R.sup.Xa and R.sup.Xb pair can combine with the carbon
atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to
the piperidinyl ring; wherein said 3-, 4-, 5-, 6-membered
monocyclic ring contains 0 N, O, and S atoms, and further wherein
said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1,
2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--NR.sup.aR.sup.a, or oxo.
[0046] In embodiment 5, the present invention provides compounds
wherein X.sup.1 is N; X.sup.2 is N; X.sup.3 is N; X.sup.4 is
CR.sup.3c; X.sup.5 is N; X.sup.6 is CR.sup.3e; and X.sup.7 is
CR.sup.3f; having the formula (Id):
##STR00007##
wherein said R.sup.Xa and R.sup.Xb pair can combine with the carbon
atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to
the piperidinyl ring; wherein said 3-, 4-, 5-, 6-membered
monocyclic ring contains 0 N, O, and S atoms, and further wherein
said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1,
2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--NR.sup.aR.sup.a, or oxo.
[0047] In embodiment 6, the present invention provides compounds
wherein X.sup.1 is CR.sup.6; X.sup.2 is CR.sup.3a; X.sup.3 is N;
X.sup.4 is N; X.sup.5 is CR.sup.3d; X.sup.6 is CR.sup.3e; and
X.sup.7 is CR.sup.3f; having the formula (Ie):
##STR00008##
wherein said R.sup.Xa and R.sup.Xb pair can combine with the carbon
atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, 6-membered monocyclic ring spiro to
the piperidinyl ring; wherein said 3-, 4-, 5-, 6-membered
monocyclic ring contains 0 N, O, and S atoms, and further wherein
said 3-, 4-, 5-, 6-membered monocyclic ring is substituted by 0, 1,
2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OR.sup.a, --OC.sub.1-4haloalk, CN,
--NR.sup.aR.sup.a, or oxo.
[0048] In embodiment 7, the present invention provides compounds in
accordance with any of the above embodiments, or pharmaceutically
acceptable salts thereof, wherein R.sup.3 is H or methyl.
[0049] In embodiment 8, the present invention provides compounds in
accordance with any of the above embodiments, or pharmaceutically
acceptable salts thereof, wherein each of R.sup.Xc, R.sup.Xd,
R.sup.Xe, R.sup.Xf, R.sup.Xg, R.sup.Xh, R.sup.Xi, R.sup.Xj,
R.sup.Xk, and R.sup.Xl is H, halo, C.sub.1-6alk, or
C.sub.1-4haloalk; and each of R.sup.Xa and R.sup.Xb pair combine
with the carbon atom attached to each of them form a saturated 3-,
4-, or 5-membered monocyclic ring spiro to the piperidinyl ring;
wherein said ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atoms
selected from O and S.
[0050] In embodiment 9, the present invention provides compounds in
accordance with any of the above embodiments, or pharmaceutically
acceptable salts thereof, wherein each of R.sup.Xc, R.sup.Xd,
R.sup.Xe, R.sup.Xf, R.sup.Xg, R.sup.Xh, R.sup.Xi, R.sup.Xj,
R.sup.Xk, and R.sup.Xl is H, methyl, or ethyl; and each of R.sup.Xa
and R.sup.Xb pair combine with the carbon atom attached to each of
them form a cyclopropyl, cyclobutyl, or cyclopentyl ring spiro to
the piperidinyl ring.
[0051] In embodiment 10, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein the group
##STR00009##
is selected from:
##STR00010##
[0052] In embodiment 11, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein the group
##STR00011##
[0053] In embodiment 12, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is --CN,
or a group --Z--R.sup.8, wherein Z is absent, --NH--,
--NHSO.sub.2--, --SO.sub.2NH--, --N.dbd.S(.dbd.O)--(R.sup.11).sub.2
(wherein the two R.sup.7 pair can alternatively combine with the
sulfur atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring
containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from
O and S), --S(.dbd.O)(.dbd.NH)--, --S--, --S(.dbd.O)--,
--SO.sub.2--, --(C.dbd.O)--, --(C.dbd.O)NH--, or --NH(C.dbd.O)--;
and
[0054] R.sup.8 is selected from:
[0055] (a) H;
[0056] (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl,
morpholinyl, pyrrolidinyl, piperazinyl,
##STR00012##
wherein each said ring is substituted by 0, 1, 2 or 3 group(s)
selected from wherein each ring is substituted by 0, 1, 2 or 3 OH,
F, methyl, --CH.sub.2OH, --C(.dbd.O)OCH.sub.3,
--C(.dbd.O)OC(CH.sub.3).sub.3, NH.sub.2, CN, and oxo; or
[0057] (c) C.sub.1-6alk substituted by 0, 1, 2 or 3 OH, F,
--C(.dbd.O)OCH.sub.3, --NH.sub.2, --NH(CH.sub.3), or
--N(CH.sub.3).sub.2.
[0058] In embodiment 13, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is --CN,
or a group --Z--R.sup.8, wherein Z is absent, --NH--,
--NHSO.sub.2--, --SO.sub.2NH--, --N.dbd.S(.dbd.O)--(R.sup.7).sub.2
(wherein the two R.sup.7 pair can alternatively combine with the
sulfur atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring
containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from
O and S), --S(.dbd.O)(.dbd.NH)--, --S--, --S(.dbd.O)--,
--SO.sub.2--, --(C.dbd.O)--, --(C.dbd.O)NH--, or --NH(C.dbd.O)--;
and
[0059] (a) R.sup.8 is H;
[0060] (b) R.sup.8 is oxetanyl, cyclopropyl; or
[0061] (c) R.sup.8 is C.sub.1-6alk substituted by 0, 1, 2 or 3 OH
group(s).
[0062] In embodiment 14, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
group --Z--R.sup.8, wherein Z is
--N.dbd.S(.dbd.O)--(R.sup.7).sub.2; wherein each R.sup.7 is
independently selected from the group consisting of H, methyl, or
isopropyl; or the two R.sup.7 pair can alternatively combine with
the sulfur atom attached to each of them to form a saturated or
partially-saturated 3-, 4-, 5-, or 6-membered monocyclic ring
containing 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected from
O and S, which is selected from:
##STR00013##
[0063] In embodiment 15, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
group --Z--R.sup.8, wherein Z is --SO.sub.2; --NHSO.sub.2--;
--SO.sub.2NH--; or --S(.dbd.O)(.dbd.NH)--; and R.sup.8 is H,
oxetanyl, cyclopropyl, or R.sup.8 is C.sub.1-6alk substituted by 0,
1, 2 or 3 OH group(s).
[0064] In embodiment 16, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
group --Z--R.sup.8, wherein Z is --NHSO.sub.2-- and R.sup.8 is
--CH.sub.2--CH.sub.2--OH.
[0065] In embodiment 17, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
group --Z--R.sup.8, wherein Z is --SO.sub.2; and R.sup.8 is
methyl.
[0066] In embodiment 18, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
group --Z--R.sup.8, wherein Z is --S(.dbd.O)(.dbd.NH)--; and
R.sup.8 is cyclopropyl.
[0067] In embodiment 19, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is
H.
[0068] In embodiment 20, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.2 is halo
or a group --Y--R.sup.9, wherein Y is absent, --NH--,
--NH--(CH.sub.2).sub.0-4--, or --O--(CH.sub.2).sub.0-4; and
[0069] R.sup.9 is a saturated, partially-saturated or unsaturated
3-, 4-, 5-, 6-, or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-,
10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N
atoms and 0 or 1 atoms selected from O and S, which is substituted
by 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C.sub.1-6alk,
C.sub.1-4haloalk, --OH, --OC.sub.1-4haloalk, CN, R.sup.10, and oxo;
or
[0070] R.sup.9 is C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5
group(s) selected from F, Cl, Br, --OH, --OC.sub.1-4haloalk, or
CN.
[0071] In embodiment 21, the present invention provides compounds
in accordance with embodiments 1-17, or pharmaceutically acceptable
salts thereof, wherein R is a saturated 5- or 6-membered monocyclic
ring wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1
O atom, and wherein each said ring is substituted by 0, 1, 2 or 3
group(s) selected from F, Cl, Br, C.sub.1-6alk, C.sub.1-4haloalk,
--OH, --OC.sub.1-4haloalk, CN, R.sup.10, and oxo.
[0072] In embodiment 22, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein
[0073] R.sup.2 is (a) halo; (b) a group --Y--R.sup.9, wherein Y is
absent; and R.sup.9 is morpholinyl, piperidinyl, azetidinyl,
pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
piperazinyl, tetrahydrofuranyl,
##STR00014## ##STR00015##
wherein each said ring is substituted by 0, 1, 2 or 3 group(s)
selected from F, Cl, Br, methyl, CF.sub.3, --OH, --OCHF.sub.2, CN,
and oxo; or (c) a group --Y--R.sup.9, wherein Y is NH, --O--,
--O--(CH.sub.2)--, --O--(CH.sub.2)--(CH.sub.2)--, or
--O--(CH.sub.2)--(CH.sub.2)--(CH.sub.2)--, and wherein R.sup.9
is
##STR00016##
or R.sup.9 is C.sub.1-6alk substituted by 0, 1, 2, 3, 4, or 5
group(s) selected from F, Cl, Br, methyl, CF.sub.3, --OH, or CN
[0074] In embodiment 23, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.2 is
morpholinyl or piperidinyl substituted by 0, 1, 2 or 3 group(s)
selected from F, Cl, Br, methyl, CF.sub.3, --OH, --OCHF.sub.2, CN,
or oxo.
[0075] In embodiment 24, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.2 is
morpholinyl substituted by 1, 2 or 3 methyl group(s)
[0076] In embodiment 25, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.2 is
piperidinyl substituted by 1, 2 or 3 fluoro group(s).
[0077] In embodiment 26, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof wherein R.sup.2 is
##STR00017##
[0078] In embodiment 27, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.2 is
methyl or --O--(CH.sub.2)--(CH.sub.2)--CF.sub.3.
[0079] In embodiment 28, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein Z is absent,
--NH--, --NHSO.sub.2--, --SO.sub.2NH--,
--N.dbd.S(.dbd.O)<(R.sup.a).sub.2 (wherein each R.sup.7 is
independently selected from the group consisting of H, methyl, or
isopropyl), --S(.dbd.O)(.dbd.NH)--, --S--, --S(.dbd.O)--,
--SO.sub.2--, --(C.dbd.O)--, --(C.dbd.O)NH--, or
--NH(C.dbd.O)--.
[0080] In embodiment 29, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.8 is
selected from (a) H; (b) C.sub.1-6alk substituted by 0, 1, 2 or 3
group(s) selected from F, Cl, Br, --OH, --OCH.sub.3, or
cyclopropyl; or (c) a saturated, partially-saturated or unsaturated
3-, 4-, 5-, 6-, or 7-membered monocyclic ring containing 0, 1, 2 or
3 N atoms and 0 or 1 atoms selected from O and S, which is
substituted by 0, 1, 2 or 3 group(s) selected from F, Cl, Br,
C.sub.1-6alk, C.sub.1-4haloalk, --C.sub.1-6alkOH, --OH,
--OCH.sub.3, --NH.sub.2, or oxo.
[0081] In embodiment 30, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.8 is
selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,
azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiazinanyl.
[0082] In embodiment 31, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3 is
H.
[0083] In embodiment 32, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.4 is
selected from (a) H; (b) C.sub.1-6alk substituted by 0, 1, 2 or 3
OH group(s); or (c) cyclopropyl.
[0084] In embodiment 33, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.4 is
methyl.
[0085] In embodiment 34, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.5 is
H.
[0086] In embodiment 35, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.6 is H or
F.
[0087] In embodiment 36, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3a is H or
F.
[0088] In embodiment 37, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3b is
H.
[0089] In embodiment 38, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3c is
H.
[0090] In embodiment 39, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3d is
H.
[0091] In embodiment 40, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3e is
H.
[0092] In embodiment 41, the present invention provides compounds
in accordance with any of the above embodiments, or
pharmaceutically acceptable salts thereof, wherein R.sup.3f is
H.
[0093] In embodiment 42, the present invention provides a compound,
or pharmaceutically acceptable salts thereof, selected from: [0094]
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0095]
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-2-methyl-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0096]
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfony-
l)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine; [0097]
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-
-6-yl)quinazolin-4-amine; [0098]
(R)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone;
[0099]
(S)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone;
[0100]
2-Hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide; [0101]
N-(4-((3,5-Dimethylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin--
7-yl)-2-hydroxyethane-1-sulfonamide; [0102]
N-(5-(6-Azaspiro[2.5]octan-6-yl)-4-((3-(3,3,3-trifluoropropoxy)phenyl)ami-
no)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide; [0103]
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6--
azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0104]
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamid-
e; [0105]
N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino-
)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonam-
ide; [0106]
N-(4-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenoxy)-5-(6-azaspiro[2.5]o-
ctan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide; [0107]
N-(1-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro-
[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide;
[0108]
(R)-2-Hydroxy-N-(4-((3-methyl-5-(2-methylmorpholino)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide; [0109]
(R)-2-Hydroxy-N-(4-((4-methyl-6-(2-methylmorpholino)pyridin-2-yl)amino)-5-
-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
[0110]
(R)-2-Hydroxy-N-(4-((6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)amino)-
-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide;
[0111]
2-Hydroxy-N-(4-((2-((1-hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimid-
in-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfo-
namide; [0112]
N-(4-((2-Fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)amino)-5-(-
6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0113]
2-Hydroxy-N-(4-((3-(2-hydroxy-2-methylpropoxy)phenyl)amino)-5-(6-a-
zaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide; [0114]
4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-N-(3-met-
hyloxetan-3-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide;
[0115]
(S)-N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)ami-
no)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-1-hydroxypropane-2-sulfo-
namide; [0116]
(R)-N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(-
6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-1-hydroxypropane-2-sulfonamide;
[0117]
N-(4-((2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)amino)-
-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonami-
de; [0118]
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)am-
ino)-8-fluoro-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethan-
e-1-sulfonamide; [0119]
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6--
azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-2-hydroxyethane-1-sul-
fonamide; [0120]
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(7--
azaspiro[3.5]nonan-7-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0121]
N-(4-((2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-5-(4,4--
dimethylazepan-1-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0122]
2-((4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)sulfonyl)ethan-1-ol;
[0123]
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)thio)-5-(6-azaspiro[-
2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0124]
7-(Azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrim-
idin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine; [0125]
N-(tert-Butyl)-3-((7-((2-hydroxyethyl)sulfonamido)-5-(6-azaspiro[2.5]octa-
n-6-yl)quinazolin-4-yl)amino)benzenesulfonamide; [0126]
N-(4-((3-(Cyclopentylsulfonyl)-4-methylphenyl)amino)-5-(6-azaspiro[2.5]oc-
tan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide; [0127]
N-(tert-Butyl)-4-((6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide; [0128]
N-(tert-Butyl)-4-(chroman-5-ylamino)-5-(6-azaspiro[2.5]octan-6-yl)quinazo-
line-7-sulfonamide; [0129]
N-(1-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-8-(6-az-
aspiro[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide;
[0130]
N-(1-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)--
8-(6-azaspiro[2.5]octan-6-yl)isoquinolin-6-yl)-2-hydroxyethane-1-sulfonami-
de; [0131]
N-(1-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(-
6-azaspiro[2.5]octan-6-yl)isoquinolin-6-yl)-2-hydroxyethane-1-sulfonamide;
[0132]
2-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-a-
zaspiro[2.5]octan-6-yl)quinazolin-7-yl)isothiazolidine 1,1-dioxide;
[0133]
N-(4-((3-(3,3-Difluoro-6-azabicyclo[3.1.1]heptan-6-yl)-5-methylphenyl)ami-
no)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfon-
amide; [0134]
N-(4-((3-(6,6-Difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-5-methylphenyl)ami-
no)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfon-
amide; [0135]
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-4-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide;
[0136]
4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-N-(2-hydroxyethy-
l)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-carboxamide; [0137]
2-((8-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-1-(6-azaspir-
o[2.5]octan-6-yl)-2,7-naphthyridin-3-yl)amino)-2-methylpropan-1-ol;
[0138]
2-((5-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-4-(6-azaspir-
o[2.5]octan-6-yl)-1,6-naphthyridin-2-yl)amino)-2-methylpropan-1-ol;
[0139]
2-((5-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-4-(6-azaspir-
o[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)amino)-2-methylpropan-1-ol;
[0140]
2-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-a-
zaspiro[2.5]octan-6-yl)quinazolin-7-yl)propan-2-ol; or [0141]
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-
-6-yl)pyrido[3,4-d]pyrimidin-4-amine.
[0142] In embodiment 43, the present invention provides a compound,
or pharmaceutically acceptable salts thereof, selected from:
TABLE-US-00001 Ex. # Chemical Structure Name 100 ##STR00018##
N-(4-((3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)amino)-
5-(6-azaspiro[2.5]octan-6-yl) quinazolin-7-yl)-2-hydroxy-
ethane-1-sulfonamide 100-1 ##STR00019##
N-(4-((3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)amino)-2-
methyl-5-(6-azaspiro[2.5]octan- 6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 101 ##STR00020##
N-(3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)-7-
(methylsulfonyl)-5-(6- azaspiro[2.5]octan-6-yl) quinazolin-4-amine
101-1 ##STR00021## N-(3-(4,4-Difluoropiperidin-
1-yl)-5-methylphenyl)-5-(6- azaspiro[2.5]octan-6-yl)
quinazolin-4-amine 102-1 ##STR00022## (R)-Cyclopropyl(4-((3-
(4,4-difluoropiperidin-1- yl)-5-methylphenyl)
amino)-5-(6-azaspiro[2.5] octan-6-yl)quinazolin-7-
yl)(imino)-16-sulfanone 102-2 ##STR00023## (S)-Cyclopropyl(4-((3-
(4,4-difluoropiperidin-1- yl)-5-methylphenyl)
amino)-5-(6-azaspiro[2.5] octan-6-yl)quinazolin-7-
yl)(imino)-16-sulfanone 103 ##STR00024## 2-Hydroxy-N-(4-((3-methyl-
5-(3,3,3-trifluoropropoxy) phenyl)amino)-5-(6-azaspiro
[2.5]octan-6-yl)quinazolin- 7-yl)ethane-1-sulfonamide 103-1
##STR00025## N-(4-((3,5-Dimethylphenyl) amino)-5-(6-azaspiro[2.5]
octan-6-yl)quinazolin-7-yl)- 2-hydroxyethane-1- sulfonamide 103-2
##STR00026## N-(5-(6-Azaspiro[2.5]octan- 6-yl)-4-((3-(3,3,3-
trifluoropropoxy)phenyl) amino)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 104 ##STR00027##
N-(4-((2-(4,4-Difluoro- piperidin-1-yl)-6-
methylpyrimidin-4-yl)amino)- 5-(6-azaspiro[2.5]octan-6-yl)
quinazolin-7-yl)-2- hydroxyethane-1-sulfonamide 105 ##STR00028##
N-(4-((2-(4,4-Difluoropiperidin- 1-yl)-6-methylpyridin-4-yl)
amino)-5-(6-azaspiro[2.5]octan- 6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 105-1 ##STR00029##
N-(4-((6-(4,4-Difluoropiperidin- 1-yl)-4-methylpyridin-2-yl)
amino)-5-(6-azaspiro[2.5]octan- 6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 105-2 ##STR00030##
N-(4-(3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenoxy)-5-(6-
azaspiro[2.5]octan-6-yl) quinazolin-7-yl)-2-hydroxy-
ethane-1-sulfonamide 106 ##STR00031##
N-(1-((3-(4,4-Difluoropiperidin- 1-yl)-5-methylphenyl)amino)-
8-(6-azaspiro[2.5]octan-6-yl) phthalazin-6-yl)-2-
hydroxyethane-1-sulfonamide
or any pharmaceutically-acceptable salt thereof.
[0143] Another aspect of the present invention is a pharmaceutical
composition comprising anew class of compounds useful for
modulating KIF18A protein alone or in a bound complex with
microtubules or pharmaceutically acceptable salts thereof.
[0144] In embodiment 44, the present invention provides
pharmaceutical compositions comprising a compound, or
pharmaceutically acceptable salts thereof, in accordance with any
one of embodiments 1-43, and a pharmaceutically acceptable diluent
or carrier.
[0145] Yet another aspect of the present invention is a method of
treating a condition that may be treated with KIF18a inhibitors,
the method comprising administering to a patient in need thereof a
therapeutically effective amount of a new class of compounds useful
for modulating KIF18A protein alone or in a bound complex with
microtubules or pharmaceutically acceptable salts thereof.
[0146] In embodiment 45, the present invention provides a method of
treating a condition that may be treated with KIF18a inhibitors,
the method comprising administering to a patient in need thereof a
therapeutically effective amount of the compound in accordance with
embodiments 1-43, or the composition according to embodiment
44.
[0147] In embodiment 46, the present invention provides the method
of embodiment 45, wherein said condition is cancer selected from
the group consisting of (a) a solid or hematologically derived
tumor selected from cancer of the cancer of the bladder,
endometrial, lung squamous cell, breast, colon, kidney, liver,
lung, small cell lung cancer, esophagus, gall-bladder, brain, head
and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and
skin, (b) a hematopoietic tumor of lymphoid lineage selected from
leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia,
B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a
hematopoietic tumor of myeloid lineage selected from acute and
chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia (d) a tumor of mesenchymal origin selected
from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central
and peripheral nervous system selected from astrocytoma,
neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer or Kaposi's sarcoma.
[0148] In a sub-embodiment 46a, the present invention provides the
method of embodiment 45, wherein said condition is cancer selected
from the group consisting of melanoma, prostate cancer, cervical
cancer, breast cancer, colon cancer, sarcoma, or leukemia. See:
Zhang C. et. al., "Kif18A is involved in human breast
carcinogenesis", Carcinogenesis, 2010 September; 31(9):1676-84.
doi: 10.1093/carcin/bgq134. Epub 2010 Jul. 1. See also: (1)
https://www.proteinatlas.org/ENSG00000121621-KIF18A/pathology; (2)
Nagahara, M. et. al., "Kinesin 18A expression: clinical relevance
to colorectal cancer progression", Int. J. Cancer: 129, 2543-2552
(2011) VC 2011 UIC; and (3) Yu, Y. et. al., "The Role of Kinesin
Family Proteins in Tumorigenesis and Progression--Potential
Biomarkers and Molecular Targets for Cancer Therapy", Cancer 2010;
116:5150-60. VC 2010 American Cancer Society.
[0149] In embodiment 47, the present invention provides a method of
reducing the size of a solid tumor in a subject, the method
comprising administering to the subject in need thereof a
therapeutically effective amount of the compound in accordance with
embodiments 1-43, or the composition according to embodiment
44.
[0150] In embodiment 48, the present invention provides a method of
treating a cell proliferation disorder in a subject, the method
comprising administering to the subject in need thereof a
therapeutically effective amount of the compound in accordance with
embodiments 1-43, or the composition according to embodiment
44.
[0151] In embodiment 49, the present invention provides a method of
inhibiting KIF18A in a cell, comprising contacting the cell with a
compound, or pharmaceutically acceptable salts thereof, in
accordance with embodiments 1-43, or the composition according to
embodiment 44.
[0152] Yet another aspect of the present invention is a method of
preparing a new class of compounds useful for modulating KIF18A
protein alone or in a bound complex with microtubules or
pharmaceutically acceptable salts thereof.
[0153] In embodiment 50, the invention provides a method of
preparing a compound of Formula (I) as described herein.
[0154] In embodiment 51, the invention provides an intermediate
compound used in the method of preparing a compound of Formula (I)
as described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0155] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of the present invention
wherein one or more atoms are replaced by atoms having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number which predominates in nature.
[0156] Examples of isotopes suitable for inclusion in the compounds
of the invention include, but are not limited to, isotopes of
hydrogen, such as .sup.2H and .sup.3H, carbon, such as .sup.11C,
.sup.13C and .sup.14C, chlorine, such as .sup.38Cl, fluorine, such
as .sup.18F, iodine, such as .sup.123I and .sup.125I, nitrogen,
such as .sup.13N and .sup.15N, oxygen, such as .sup.15O, .sup.17O
and .sup.18O, phosphorus, such as .sup.32P, and sulphur, such as
.sup.35S.
[0157] Certain isotopically-labelled compounds of the present
invention, for example, those incorporating a radioactive isotope,
are useful in drug and/or substrate tissue distribution studies.
The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e.
.sup.14C, are particularly useful for this purpose in view of their
ease of incorporation and ready means of detection.
[0158] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0159] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0160] Isotopically-labeled compounds of the present invention can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples and Preparations using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
[0161] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0162] Specific embodiments of the present invention include the
compounds exemplified in the Examples below and their
pharmaceutically acceptable salts, complexes, solvates, polymorphs,
stereoisomers, metabolites, prodrugs, and other derivatives
thereof.
[0163] Unless otherwise specified, the following definitions apply
to terms found in the specification and claims:
[0164] "C.sub..alpha.-.beta.alk" means an alkyl group comprising a
minimum of .alpha. and a maximum of .beta. carbon atoms in a
branched or linear relationship or any combination of the three,
wherein .alpha. and .beta. represent integers. The alkyl groups
described in this section may also contain one or two double or
triple bonds. A designation of C.sub.0alk indicates a direct bond.
Examples of C.sub.1-6alkyl include, but are not limited to the
following:
##STR00032##
[0165] "Benzo group", alone or in combination, means the divalent
radical C.sub.4H.sub.4.dbd., one representation of which is
--CH.dbd.CH--CH.dbd.CH--, that when vicinally attached to another
ring forms a benzene-like ring--for example tetrahydronaphthylene,
indole and the like.
[0166] The terms "oxo" and "thioxo" represent the groups .dbd.O (as
in carbonyl) and .dbd.S (as in thiocarbonyl), respectively.
[0167] "Halo" or "halogen" means a halogen atom selected from F,
Cl, Br and I.
[0168] "C.sub..alpha.-.beta.haloalk" means an alk group, as
described above, wherein any number--at least one--of the hydrogen
atoms attached to the alk chain are replaced by F, Cl, Br or I.
[0169] The group N(R.sup.a)R.sup.a and the like include
substituents where the two R.sup.a groups together form a ring,
optionally including a N, O or S atom, and include groups such
as
##STR00033##
[0170] The group N(C.sub..alpha.-.beta.alk)
C.sub..alpha.-.beta.alk, wherein .alpha. and .beta. are as defined
above, include substituents where the two C.sub..alpha.-.beta.alk
groups together form a ring, optionally including a N, O or S atom,
and include groups such as:
##STR00034##
[0171] "Bicyclic ring" means a group that features two joined
rings. A bicyclic ring can be carbocyclic (all of the ring atoms
are carbons), or heterocyclic (the rings atoms consist, for
example, 1, 2 or 3 heteroatoms, such as N, O, or S, in addition to
carbon atoms). The two rings can both be aliphatic (e.g. decalin
and norbornane), or can be aromatic (e.g. naphthalene), or a
combination of aliphatic and aromatic (e.g. tetralin).
[0172] Bicyclic rings include:
[0173] (a) spirocyclic compounds, wherein the two rings share only
one single atom, the spiro atom, which is usually a quaternary
carbon. Examples of spirocyclic compound include, but are not
limited to:
##STR00035##
[0174] (b) fused bicyclic compounds, wherein two rings share two
adjacent atoms. In other words, the rings share one covalent bond,
i.e. the bridgehead atoms are directly connected (e.g.
.alpha.-thujene and decalin). Examples of fused bicyclic rings
include, but are not limited to:
##STR00036##
[0175] (c) bridged bicyclic compounds, wherein the two rings share
three or more atoms, separating the two bridgehead atoms by a
bridge containing at least one atom. For example, norbornane, also
known as bicyclo[2.2.1]heptane, can be thought of as a pair of
cyclopentane rings each sharing three of their five carbon atoms.
Examples of bridged bicyclic rings include, but are not limited
to:
##STR00037##
[0176] "Carbocycle" or "Carbocyclic" means a ring comprising by
itself or in combination with other terms, represents, unless
otherwise stated, cyclic version of "C.sub..alpha.-.beta.alk".
Examples of carbocycle include cyclopentyl, cyclohexyl,
1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene,
cyclohexylene and the like.
[0177] "Heterocycle" or "Heterocyclic" means a ring comprising at
least one carbon atom and at least one other atom selected from N,
O and S. Examples of heterocycles that may be found in the claims
include, but are not limited to, the following:
##STR00038## ##STR00039##
[0178] "Pharmaceutically-acceptable salt" means a salt prepared by
conventional means, and are well known by those skilled in the art.
The "pharmacologically acceptable salts" include basic salts of
inorganic and organic acids, including but not limited to
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic
acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric
acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
phenylacetic acid, mandelic acid and the like. When compounds of
the invention include an acidic function such as a carboxy group,
then suitable pharmaceutically acceptable cation pairs for the
carboxy group are well known to those skilled in the art and
include alkaline, alkaline earth, ammonium, quaternary ammonium
cations and the like. For additional examples of "pharmacologically
acceptable salts," see infra and Berge et al., J. Pharm. Sci. 66:1
(1977).
[0179] "Saturated, partially-saturated or unsaturated" includes
substituents saturated with hydrogens, substituents completely
unsaturated with hydrogens and substituents partially saturated
with hydrogens.
[0180] "Leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol or an
alcohol nucleophile. Such leaving groups are well known in the art.
Examples of such leaving groups include, but are not limited to,
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,
tosylates and the like. Preferred leaving groups are indicated
herein where appropriate.
[0181] "Protecting group" generally refers to groups well known in
the art which are used to prevent selected reactive groups, such as
carboxy, amino, hydroxy, mercapto and the like, from undergoing
undesired reactions, such as nucleophilic, electrophilic,
oxidation, reduction and the like. Preferred protecting groups are
indicated herein where appropriate. Examples of amino protecting
groups include, but are not limited to, aralkyl, substituted
aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl,
allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,
silyl and the like. Examples of aralkyl include, but are not
limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl,
which can be optionally substituted with halogen, alkyl, alkoxy,
hydroxy, nitro, acylamino, acyl and the like, and salts, such as
phosphonium and ammonium salts. Examples of aryl groups include
phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),
phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl
or substituted cycloalkylenylalkyl radicals, preferably have 6-10
carbon atoms, include, but are not limited to, cyclohexenyl methyl
and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl
groups include benzyloxycarbonyl, t-butoxycarbonyl,
iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,
trifluoroacetyl, trichloro acetyl, phthaloyl and the like. A
mixture of protecting groups can be used to protect the same amino
group, such as a primary amino group can be protected by both an
aralkyl group and an aralkoxycarbonyl group. Amino protecting
groups can also form a heterocyclic ring with the nitrogen to which
they are attached, for example, 1,2-bis(methylene)benzene,
phthalimidyl, succinimidyl, maleimidyl and the like and where these
heterocyclic groups can further include adjoining aryl and
cycloalkyl rings. In addition, the heterocyclic groups can be
mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino
groups may also be protected against undesired reactions, such as
oxidation, through the formation of an addition salt, such as
hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the
like. Many of the amino protecting groups are also suitable for
protecting carboxy, hydroxy and mercapto groups. For example,
aralkyl groups. Alkyl groups are also suitable groups for
protecting hydroxy and mercapto groups, such as tert-butyl.
[0182] Silyl protecting groups are silicon atoms optionally
substituted by one or more alkyl, aryl and aralkyl groups. Suitable
silyl protecting groups include, but are not limited to,
trimethylsilyl, triethylsilyl, triisopropylsilyl,
tert-butyldimethylsilyl, dimethylphenylsilyl,
1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and
diphenylmethylsilyl. Silylation of an amino groups provide mono- or
di-silylamino groups. Silylation of aminoalcohol compounds can lead
to a N,N,O-trisilyl derivative. Removal of the silyl function from
a silyl ether function is readily accomplished by treatment with,
for example, a metal hydroxide or ammonium fluoride reagent, either
as a discrete reaction step or in situ during a reaction with the
alcohol group. Suitable silylating agents are, for example,
trimethylsilyl chloride, tert-butyldimethylsilyl chloride,
phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or
their combination products with imidazole or DMF. Methods for
silylation of amines and removal of silyl protecting groups are
well known to those skilled in the art. Methods of preparation of
these amine derivatives from corresponding amino acids, amino acid
amides or amino acid esters are also well known to those skilled in
the art of organic chemistry including amino acid/amino acid ester
or aminoalcohol chemistry.
[0183] Protecting groups are removed under conditions which will
not affect the remaining portion of the molecule. These methods are
well known in the art and include acid hydrolysis, hydrogenolysis
and the like. A preferred method involves removal of a protecting
group, such as removal of a benzyloxycarbonyl group by
hydrogenolysis utilizing palladium on carbon in a suitable solvent
system such as an alcohol, acetic acid, and the like or mixtures
thereof. A t-butoxycarbonyl protecting group can be removed
utilizing an inorganic or organic acid, such as HCl or
trifluoroacetic acid, in a suitable solvent system, such as dioxane
or methylene chloride. The resulting amino salt can readily be
neutralized to yield the free amine. Carboxy protecting group, such
as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the
like, can be removed under hydrolysis and hydrogenolysis conditions
well known to those skilled in the art.
[0184] It should be noted that compounds of the invention may
contain groups that may exist in tautomeric forms, such as cyclic
and acyclic amidine and guanidine groups, heteroatom substituted
heteroaryl groups (Y'=O, S, NR), and the like, which are
illustrated in the following examples:
##STR00040##
and though one form is named, described, displayed and/or claimed
herein, all the tautomeric forms are intended to be inherently
included in such name, description, display and/or claim.
[0185] Prodrugs of the compounds of this invention are also
contemplated by this invention. A prodrug is an active or inactive
compound that is modified chemically through in vivo physiological
action, such as hydrolysis, metabolism and the like, into a
compound of this invention following administration of the prodrug
to a patient. The suitability and techniques involved in making and
using prodrugs are well known by those skilled in the art. For a
general discussion of prodrugs involving esters see Svensson and
Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of
Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion
include a variety of esters, such as alkyl (for example, methyl,
ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example,
benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example,
pivaloyloxymethyl). Amines have been masked as
arylcarbonyloxymethyl substituted derivatives which are cleaved by
esterases in vivo releasing the free drug and formaldehyde
(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an
acidic NH group, such as imidazole, imide, indole and the like,
have been masked with N-acyloxymethyl groups (Bundgaard Design of
Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as
esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses
Mannich-base hydroxamic acid prodrugs, their preparation and
use.
[0186] The specification and claims contain listing of species
using the language "selected from . . . and . . . " and "is . . .
or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups as needed.
Pharmaceutical Compositions, Dosing, and Routes of
Administration
[0187] Also provided herein are pharmaceutical compositions that
includes a compound as disclosed herein, together with a
pharmaceutically acceptable excipient, such as, for example, a
diluent or carrier. Compounds and pharmaceutical compositions
suitable for use in the present invention include those wherein the
compound can be administered in an effective amount to achieve its
intended purpose. Administration of the compound described in more
detail below.
[0188] Suitable pharmaceutical formulations can be determined by
the skilled artisan depending on the route of administration and
the desired dosage. See, e.g., Remington's Pharmaceutical Sciences,
1435-712 (18th ed., Mack Publishing Co, Easton, Pa., 1990).
Formulations may influence the physical state, stability, rate of
in vivo release and rate of in vivo clearance of the administered
agents. Depending on the route of administration, a suitable dose
may be calculated according to body weight, body surface areas or
organ size. Further refinement of the calculations necessary to
determine the appropriate treatment dose is routinely made by those
of ordinary skill in the art without undue experimentation,
especially in light of the dosage information and assays disclosed
herein as well as the pharmacokinetic data obtainable through
animal or human clinical trials.
[0189] The phrases "pharmaceutically acceptable" or
"pharmacologically acceptable" refer to molecular entities and
compositions that do not produce adverse, allergic, or other
untoward reactions when administered to an animal or a human. As
used herein, "pharmaceutically acceptable e" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents and the like. The
use of such excipients for pharmaceutically active substances is
well known in the art. Except insofar as any conventional media or
agent is incompatible with the therapeutic compositions, its use in
therapeutic compositions is contemplated. Supplementary active
ingredients also can be incorporated into the compositions. In
exemplary embodiments, the formulation may comprise corn syrup
solids, high-oleic safflower oil, coconut oil, soy oil, L-leucine,
calcium phosphate tribasic, L-tyrosine, L-proline, L-lysine
acetate, DATEM (an emulsifier), L-glutamine, L-valine, potassium
phosphate dibasic, L-isoleucine, L-arginine, L-alanine, glycine,
L-asparagine monohydrate, L-serine, potassium citrate, L-threonine,
sodium citrate, magnesium chloride, L-histidine, L-methionine,
ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine
dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride,
taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc
sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride,
niacinamide, mixed tocopherols, calcium pantothenate, cupric
sulfate, thiamine chloride hydrochloride, vitamin A palmitate,
manganese sulfate, riboflavin, pyridoxine hydrochloride, folic
acid, beta-carotene, potassium iodide, phylloquinone, biotin,
sodium selenate, chromium chloride, sodium molybdate, vitamin D3
and cyanocobalamin.
[0190] The compound can be present in a pharmaceutical composition
as a pharmaceutically acceptable salt. As used herein,
"pharmaceutically acceptable salts" include, for example base
addition salts and acid addition salts.
[0191] Pharmaceutically acceptable base addition salts may be
formed with metals or amines, such as alkali and alkaline earth
metals or organic amines. Pharmaceutically acceptable salts of
compounds may also be prepared with a pharmaceutically acceptable
cation. Suitable pharmaceutically acceptable cations are well known
to those skilled in the art and include alkaline, alkaline earth,
ammonium and quaternary ammonium cations. Carbonates or hydrogen
carbonates are also possible. Examples of metals used as cations
are sodium, potassium, magnesium, ammonium, calcium, or ferric, and
the like. Examples of suitable amines include isopropylamine,
trimethylamine, histidine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, dicyclohexylamine,
ethylenediamine, N-methylglucamine, and procaine.
[0192] Pharmaceutically acceptable acid addition salts include
inorganic or organic acid salts. Examples of suitable acid salts
include the hydrochlorides, formates, acetates, citrates,
salicylates, nitrates, phosphates. Other suitable pharmaceutically
acceptable salts are well known to those skilled in the art and
include, for example, formic, acetic, citric, oxalic, tartaric, or
mandelic acids, hydrochloric acid, hydrobromic acid, sulfuric acid
or phosphoric acid; with organic carboxylic, sulfonic, sulfo or
phospho acids or N-substituted sulfamic acids, for example acetic
acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid,
succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,
fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid,
gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, salicylic acid,
4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic
acid, embonic acid, nicotinic acid or isonicotinic acid; and with
amino acids, such as the 20 alpha amino acids involved in the
synthesis of proteins in nature, for example glutamic acid or
aspartic acid, and also with phenylacetic acid, methanesulfonic
acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane
1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic
acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid,
2- or 3-phosphoglycerate, glucose 6-phosphate, N-cyclohexylsulfamic
acid (with the formation of cyclamates), or with other acid organic
compounds, such as ascorbic acid.
[0193] Pharmaceutical compositions containing the compounds
disclosed herein can be manufactured in a conventional manner,
e.g., by conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping,
or lyophilizing processes. Proper formulation is dependent upon the
route of administration chosen.
[0194] For oral administration, suitable compositions can be
formulated readily by combining a compound disclosed herein with
pharmaceutically acceptable excipients such as carriers well known
in the art. Such excipients and carriers enable the present
compounds to be formulated as tablets, pills, dragees, capsules,
liquids, gels, syrups, slurries, suspensions and the like, for oral
ingestion by a patient to be treated. Pharmaceutical preparations
for oral use can be obtained by adding a compound as disclosed
herein with a solid excipient, optionally grinding a resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients include, for example, fillers and
cellulose preparations. If desired, disintegrating agents can be
added. Pharmaceutically acceptable ingredients are well known for
the various types of formulation and may be for example binders
(e.g., natural or synthetic polymers), lubricants, surfactants,
sweetening and flavoring agents, coating materials, preservatives,
dyes, thickeners, adjuvants, antimicrobial agents, antioxidants and
carriers for the various formulation types.
[0195] When a therapeutically effective amount of a compound
disclosed herein is administered orally, the composition typically
is in the form of a solid (e.g., tablet, capsule, pill, powder, or
troche) or a liquid formulation (e.g., aqueous suspension,
solution, elixir, or syrup).
[0196] When administered in tablet form, the composition can
additionally contain a functional solid and/or solid carrier, such
as a gelatin or an adjuvant. The tablet, capsule, and powder can
contain about 1 to about 95% compound, and preferably from about 15
to about 90% compound.
[0197] When administered in liquid or suspension form, a functional
liquid and/or a liquid carrier such as water, petroleum, or oils of
animal or plant origin can be added. The liquid form of the
composition can further contain physiological saline solution,
sugar alcohol solutions, dextrose or other saccharide solutions, or
glycols. When administered in liquid or suspension form, the
composition can contain about 0.5 to about 90% by weight of a
compound disclosed herein, and preferably about 1 to about 50% of a
compound disclosed herein. In one embodiment contemplated, the
liquid carrier is non-aqueous or substantially non-aqueous. For
administration in liquid form, the composition may be supplied as a
rapidly-dissolving solid formulation for dissolution or suspension
immediately prior to administration.
[0198] When a therapeutically effective amount of a compound
disclosed herein is administered by intravenous, cutaneous, or
subcutaneous injection, the composition is in the form of a
pyrogen-free, parenterally acceptable aqueous solution. The
preparation of such parenterally acceptable solutions, having due
regard to pH, isotonicity, stability, and the like, is within the
skill in the art. A preferred composition for intravenous,
cutaneous, or subcutaneous injection typically contains, in
addition to a compound disclosed herein, an isotonic vehicle. Such
compositions may be prepared for administration as solutions of
free base or pharmacologically acceptable salts in water suitably
mixed with a surfactant, such as hydroxypropylcellulose.
Dispersions also can be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations can optionally
contain a preservative to prevent the growth of microorganisms.
[0199] Injectable compositions can include sterile aqueous
solutions, suspensions, or dispersions and sterile powders for the
extemporaneous preparation of sterile injectable solutions,
suspensions, or dispersions. In all embodiments the form must be
sterile and must be fluid to the extent that easy syringability
exists. It must be stable under the conditions of manufacture and
storage and must resist the contaminating action of microorganisms,
such as bacteria and fungi, by optional inclusion of a
preservative. The carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (e.g., glycerol,
propylene glycol, and liquid polyethylene glycol, and the like),
suitable mixtures thereof, and vegetable oils. In one embodiment
contemplated, the carrier is non-aqueous or substantially
non-aqueous. The proper fluidity can be maintained, for example, by
the use of a coating, such as lecithin, by the maintenance of the
required particle size of the compound in the embodiment of
dispersion and by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many embodiments, it will be preferable to include isotonic agents,
for example, sugars or sodium chloride. Prolonged absorption of the
injectable compositions can be brought about by the use in the
compositions of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0200] Sterile injectable solutions are prepared by incorporating
the active compounds in the required amount in the appropriate
solvent with various of the other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the embodiment of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum-drying and freeze-drying techniques which
yield a powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof.
[0201] Slow release or sustained release formulations may also be
prepared in order to achieve a controlled release of the active
compound in contact with the body fluids in the GI tract, and to
provide a substantially constant and effective level of the active
compound in the blood plasma. For example, release can be
controlled by one or more of dissolution, diffusion, and
ion-exchange. In addition, the slow release approach may enhance
absorption via saturable or limiting pathways within the GI tract.
For example, the compound may be embedded for this purpose in a
polymer matrix of a biological degradable polymer, a water-soluble
polymer or a mixture of both, and optionally suitable surfactants.
Embedding can mean in this context the incorporation of
micro-particles in a matrix of polymers. Controlled release
formulations are also obtained through encapsulation of dispersed
micro-particles or emulsified micro-droplets via known dispersion
or emulsion coating technologies.
[0202] For administration by inhalation, compounds of the present
invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant. In the embodiment of a pressurized
aerosol, the dosage unit can be determined by providing a valve to
deliver a metered amount. Capsules and cartridges of, e.g.,
gelatin, for use in an inhaler or insufflator can be formulated
containing a powder mix of the compound and a suitable powder base
such as lactose or starch.
[0203] The compounds disclosed herein can be formulated for
parenteral administration by injection (e.g., by bolus injection or
continuous infusion). Formulations for injection can be presented
in unit dosage form (e.g., in ampules or in multidose containers),
with an added preservative. The compositions can take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and can contain formulatory agents such as suspending, stabilizing,
and/or dispersing agents.
[0204] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the compounds in water-soluble form.
Additionally, suspensions of the compounds can be prepared as
appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils or synthetic fatty acid
esters. Aqueous injection suspensions can contain substances which
increase the viscosity of the suspension. Optionally, the
suspension also can contain suitable stabilizers or agents that
increase the solubility of the compounds and allow for the
preparation of highly concentrated solutions. Alternatively, a
present composition can be in powder form for constitution with a
suitable vehicle (e.g., sterile pyrogen-free water) before use.
[0205] Compounds disclosed herein also can be formulated in rectal
compositions, such as suppositories or retention enemas (e.g.,
containing conventional suppository bases). In addition to the
formulations described previously, the compounds also can be
formulated as a depot preparation. Such long-acting formulations
can be administered by implantation (e.g., subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds can be formulated with suitable polymeric or
hydrophobic materials (for example, as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0206] In particular, a compound disclosed herein can be
administered orally, buccally, or sublingually in the form of
tablets containing excipients, such as starch or lactose, or in
capsules or ovules, either alone or in admixture with excipients,
or in the form of elixirs or suspensions containing flavoring or
coloring agents. Such liquid preparations can be prepared with
pharmaceutically acceptable additives, such as suspending agents. A
compound also can be injected parenterally, for example,
intravenously, intramuscularly, subcutaneously, or intracoronarily.
For parenteral administration, the compound is best used in the
form of a sterile aqueous solution which can contain other
substances, for example, salts, or sugar alcohols, such as
mannitol, or glucose, to make the solution isotonic with blood.
[0207] For veterinary use, a compound disclosed herein is
administered as a suitably acceptable formulation in accordance
with normal veterinary practice. The veterinarian can readily
determine the dosing regimen and route of administration that is
most appropriate for a particular animal.
[0208] In some embodiments, all the necessary components for the
treatment of KIF18A-related disorder using a compound as disclosed
herein either alone or in combination with another agent or
intervention traditionally used for the treatment of such disease
may be packaged into a kit. Specifically, the present invention
provides a kit for use in the therapeutic intervention of the
disease comprising a packaged set of medicaments that include the
compound disclosed herein as well as buffers and other components
for preparing deliverable forms of said medicaments, and/or devices
for delivering such medicaments, and/or any agents that are used in
combination therapy with the compound disclosed herein, and/or
instructions for the treatment of the disease packaged with the
medicaments. The instructions may be fixed in any tangible medium,
such as printed paper, or a computer readable magnetic or optical
medium, or instructions to reference a remote computer data source
such as a world wide web page accessible via the internet.
[0209] A "therapeutically effective amount" means an amount
effective to treat or to prevent development of, or to alleviate
the existing symptoms of, the subject being treated. Determination
of the effective amounts is well within the capability of those
skilled in the art, especially in light of the detailed disclosure
provided herein. Generally, a "therapeutically effective dose"
refers to that amount of the compound that results in achieving the
desired effect. For example, in one preferred embodiment, a
therapeutically effective amount of a compound disclosed herein
decreases KIF18A activity by at least 5%, compared to control, at
least 10%, at least 15%, at least 20%, at least 25%, at least 30%,
at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, or at least 90%.
[0210] The amount of compound administered can be dependent on the
subject being treated, on the subject's age, health, sex, and
weight, the kind of concurrent treatment (if any), severity of the
affliction, the nature of the effect desired, the manner and
frequency of treatment, and the judgment of the prescribing
physician. The frequency of dosing also can be dependent on
pharmacodynamic effects on arterial oxygen pressures. While
individual needs vary, determination of optimal ranges of effective
amounts of the compound is within the skill of the art. Such doses
may be administered in a single dose or it may be divided into
multiple doses.
[0211] The terms "cancer" and "cancerous" when used herein refer to
or describe the physiological condition in mammals that is
typically characterized by unregulated cell growth. Examples of
cancer include, without limitation, carcinoma, lymphoma, sarcoma,
blastoma and leukemia. More particular examples of such cancers
include squamous cell carcinoma, lung cancer, pancreatic cancer,
cervical cancer, bladder cancer, hepatoma, breast cancer, colon
carcinoma, and head and neck cancer, ovarian cancer, and
endometrial cancer. While the term "cancer" as used herein is not
limited to any one specific form of the disease, it is believed
that the methods of the invention will be particularly effective
for cancers which are found to be accompanied by unregulated levels
of KIF18A or dependent on KIF18A for proper chromosome segregation
and survival in the mammal.
[0212] The terms "treat", "treating" and "treatment" as used herein
refer to therapy, including without limitation, curative therapy,
prophylactic therapy, and preventative therapy. Prophylactic
treatment generally constitutes either preventing the onset of
disorders altogether or delaying the onset of a pre-clinically
evident stage of disorders in individuals.
[0213] The term "patient", "subject", or "mammal" as used herein
refers to any "patient", "subject", or "mammal" including humans,
cows, horses, dogs and cats. In one embodiment of the invention,
the mammal is a human.
[0214] The term "comprising" is meant to be open ended, including
the indicated component(s) but not excluding other elements.
[0215] The terms "Formula I" include any sub formulas.
Methods of Using KIF18A Inhibitors
[0216] The present disclosure provides compounds having MT-based
KIF18A modulatory activity in general, and inhibitory activity in
particular. In one embodiment of the invention, there is provided a
method of modulating KIF18A protein in a subject, the method
comprising administering to the subject an effective dosage amount
of a compound of Formulas I. As such, the compounds of the
invention may be used to treat cellular proliferation disorders,
including uncontrolled cell growth, aberrant cell cycle regulation,
centrosome abnormalities (structural and or numeric,
fragmentation). Other diseases or disorders associated with the
accumulation of extra centrosomes (>2) include human
papillomavirus (HPV) infection, including HPV-associated
neoplasias. The compounds are also useful for cilia-related
diseases as well as ablating haploid germ cell population which
could be used as a male contraceptive.
[0217] In addition, compounds of the invention are useful for, but
not limited to, the prevention or treatment of cancer and other
KIF18A-mediated diseases or disorders. For example, compounds of
the invention would be useful for the treatment of various solid
and hematologically derived tumors, such as carcinomas, including,
without limitation, cancer of the bladder, breast, colon, kidney,
liver, lung (including squamous cell and small cell lung cancer),
esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid,
prostate, and skin (including squamous cell carcinoma);
hematopoietic tumors of lymphoid lineage (including leukemia, acute
lymphocitic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, hairy cell lymphoma and Burkett's lymphoma);
hematopoietic tumors of myeloid lineage (including acute and
chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia); tumors of mesenchymal origin (including
fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft
tissue and bone); tumors of the central and peripheral nervous
system (including astrocytoma, neuroblastoma, glioma and
schwannomas); and other tumors (including melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's
sarcoma).
[0218] The compounds of the invention are also useful in the
treatment of cancer related indications such as solid tumors,
sarcomas (especially Ewing's sarcoma and osteosarcoma),
retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic
malignancies, including leukemia and lymphoma, tumor-induced
pleural or pericardial effusions, and malignant ascites.
[0219] Based on the ability to modulate kinesin impacting
angiogenesis, the compounds of the invention are also useful in
treatment and therapy of proliferative diseases. Particularly,
these compounds can be used for the treatment of an inflammatory
disease, especially of manifestations at the locomotor apparatus,
such as various inflammatory rheumatoid diseases, especially
chronic polyarthritis including rheumatoid arthritis, juvenile
arthritis or psoriasis arthropathy; paraneoplastic syndrome or
tumor-induced inflammatory diseases, turbid effusions,
collagenosis, such as systemic Lupus erythematosus, poly-myositis,
dermato-myositis, systemic sclerodermia or mixed collagenosis;
postinfectious arthritis (where no living pathogenic organism can
be found at or in the affected part of the body), seronegative
spondylarthritis, such as spondylitis ankylosans; vasculitis,
sarcoidosis, or arthrosis; or further any combinations thereof.
[0220] The compounds of the invention can also be used as active
agents against such disease states as arthritis, atherosclerosis,
psoriasis, hemangiomas, myocardial angiogenesis, coronary and
cerebral collaterals, ischemic limb angiogenesis, wound healing,
peptic ulcer Helicobacter related diseases, fractures, cat scratch
fever, rubeosis, neovascular glaucoma and retinopathies such as
those associated with diabetic retinopathy or macular degeneration.
In addition, some of these compounds can be used as active agents
against solid tumors, malignant ascites, hematopoietic cancers and
hyperproliferative disorders such as thyroid hyperplasia
(especially Grave's disease), and cysts (such as hypervascularity
of ovarian stroma, characteristic of polycystic ovarian syndrome
(Stein-Leventhal syndrome)) since such diseases require a
proliferation of blood vessel cells for growth and/or
metastasis.
[0221] Besides being useful for human treatment, these compounds
are useful for veterinary treatment of companion animals, exotic
animals and farm animals, including mammals, rodents, and the like.
For example, animals including horses, dogs, and cats may be
treated with compounds provided by the invention.
Combinations
[0222] While the compounds of the invention can be dosed or
administered as the sole active pharmaceutical agent, they can also
be used in combination with one or more compounds of the invention
or in conjunction with other agents. When administered as a
combination, the therapeutic agents can be formulated as separate
compositions that are administered simultaneously or sequentially
at different times, or the therapeutic agents can be given as a
single composition.
[0223] The phrase "co-therapy" (or "combination-therapy"), in
defining use of a compound of the present invention and another
pharmaceutical agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[0224] Specifically, the administration of compounds of the present
invention may be in conjunction with additional therapies known to
those skilled in the art in the prevention or treatment of cancer,
such as with radiation therapy, small molecule targeted agents
(e.g. PARP inhibitors, kinase inhibitors), therapeutic antibodies
(e.g. naked and drug-conjugate) immunotherapy antibodies
(checkpoint inhibitors, bi-specific T-cell engagers) with
neoplastic or cytotoxic agents.
[0225] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the accepted dosage
ranges. Compounds of Formula I may also be administered
sequentially with known anticancer or cytotoxic agents when a
combination formulation is inappropriate. The invention is not
limited in the sequence of administration; compounds of the
invention may be administered either prior to, simultaneous with or
after administration of the known anticancer or cytotoxic
agent.
[0226] There are large numbers of anticancer agents available in
commercial use, in clinical evaluation and in pre-clinical
development, which would be selected for treatment of neoplasia by
combination drug chemotherapy. Such agents fall into several major
categories such as antibiotic-type agents, alkylating and
alkylating-like agents, antimitotic agents, targeted small molecule
agents, antimetabolite agents, hormonal agents, immunological
agents, anti-angiogenic agents, interferon-type agents and a
category of miscellaneous agents.
[0227] The present disclosure also provides methods for combination
therapies in which an agent known to modulate other pathways, or
other components of the same pathway, or even overlapping sets of
target enzymes are used in combination with a compound of the
present disclosure, or a pharmaceutically acceptable salt thereof.
In one aspect, such therapy includes but is not limited to the
combination of one or more compounds of the disclosure with
chemotherapeutic agents, therapeutic antibodies, targeted small
molecule agents, and radiation treatment, to provide a synergistic
or additive therapeutic effect.
[0228] Many chemotherapeutics are presently known in the art and
can be used in combination with the compounds of the disclosure. In
some embodiments, the chemotherapeutic is selected from the group
consisting of antimitotic agents, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
angiogenesis inhibitors, and anti-androgens. Non-limiting examples
are chemotherapeutic agents, cytotoxic agents, and non-peptide
small molecules such as Gleevec.RTM. (Imatinib Mesylate),
Kyprolis.RTM. (carfilzomib), Velcade.RTM. (bortezomib), Casodex
(bicalutamide), Iressa.RTM. (gefitinib), and Adriamycin as well as
a host of chemotherapeutic agents. Non-limiting examples of
chemotherapeutic agents include alkylating agents such as thiotepa
and cyclosphosphamide (CYTOXAN.TM.); alkyl sulfonates such as
busulfan, improsulfan and piposulfan; aziridines such as benzodopa,
carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including altretamine, triethylenemelamine,
trietylenephosphoramide, triethylenethiophosphaoramide and
trimethylolomelamine;
[0229] nitrogen mustards such as chlorambucil, chlornaphazine,
cholophosphamide, estramustine, ifosfamide, mechlorethamine,
mechlorethamine oxide hydrochloride, melphalan, novembichin,
phenesterine, prednimustine, trofosfamide, uracil mustard;
nitrosureas such as carmustine, chlorozotocin, fotemustine,
lomustine, nimustine, ranimustine; antibiotics such as
aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,
cactinomycin, calicheamicin, carabicin, carminomycin,
carzinophilin, Casodex.TM., chromomycins, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin,
epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins,
mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogues such as denopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogs such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine, androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine; diaziquone; elfomithine; elliptinium acetate;
etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;
mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;
phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSK; razoxane; sizofiran; spirogermanium; tenuazonic
acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethan;
vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;
pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide;
thiotepa; taxanes, e.g. paclitaxel and docetaxel, Nab-paclitaxel;
retinoic acid; esperamicins; capecitabine; and pharmaceutically
acceptable salts, acids or derivatives of any of the above.
[0230] Also included as suitable chemotherapeutic cell conditioners
are anti-hormonal agents that act to regulate or inhibit hormone
action on tumors such as anti-estrogens including for example
tamoxifen, (Nolvadex.TM.), raloxifene, aromatase inhibiting
4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY
117018, onapristone, and toremifene (Fareston); and anti-androgens
such as flutamide, nilutamide, bicalutamide, leuprolide, and
goserelin; chlorambucil; gemcitabine; 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin,
oxaliplatin, carboplatin; etoposide (VP-16); ifosfamide; mitomycin
C; mitoxantrone; vinblastine vincristine; vinorelbine; navelbine;
novantrone; teniposide; daunomycin; aminopterin; xeloda;
ibandronate; topotecan; camptothecin-11 (CPT-11); topoisomerase
inhibitor RFS 2000; difluoromethylornithine (DMFO),
[0231] Where desired, the compounds or pharmaceutical composition
of the present disclosure can be used in combination with commonly
prescribed anti-cancer drugs such as Herceptin.RTM., Avastin.RTM.,
Erbitux.RTM., Rituxan.RTM., Taxol.RTM., Abraxane, Arimidex.RTM.,
Taxotere.RTM., ABVD, AVICINE, Abagovomab, Acridine carboxamide,
Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin,
Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone,
Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic,
Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine,
Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin,
Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin,
cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid,
Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,
Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine,
Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod,
Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide,
Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine,
Nedaplatin, Olaparib, Talazoparib, Niraparib, Ortataxel, PAC-1,
Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod,
Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V,
Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,
Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,
Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or
Zosuquidar, CDK4/6 inhibitors (Palbociclib, Ibrance; Ribociclib,
Kisqali; Abemaciclib, Verzenio).
[0232] This disclosure further relates to a method for using the
compounds or pharmaceutical compositions provided herein, in
combination with radiation therapy for inhibiting abnormal cell
growth or treating the hyperproliferative disorder in the mammal.
Techniques for administering radiation therapy are known in the
art, and these techniques can be used in the combination therapy
described herein. The administration of the compound of the
disclosure in this combination therapy can be determined as
described herein.
[0233] Radiation therapy can be administered through one of several
methods, or a combination of methods, including without limitation
external-beam therapy, internal radiation therapy, implant
radiation, stereotactic radiosurgery, systemic radiation therapy,
radiotherapy and permanent or temporary interstitial brachytherapy.
The term "brachytherapy," as used herein, refers to radiation
therapy delivered by a spatially confined radioactive material
inserted into the body at or near a tumor or other proliferative
tissue disease site. The term is intended without limitation to
include exposure to radioactive isotopes (e.g. At-211, I-131,
I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive
isotopes of Lu). Suitable radiation sources for use as a cell
conditioner of the present disclosure include both solids and
liquids. By way of non-limiting example, the radiation source can
be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid
source, I-125 as a solid source, or other radionuclides that emit
photons, beta particles, gamma radiation, or other therapeutic
rays. The radioactive material can also be a fluid made from any
solution of radionuclide(s), e.g., a solution of I-125 or I-131, or
a radioactive fluid can be produced using a slurry of a suitable
fluid containing small particles of solid radionuclides, such as
Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a
gel or radioactive micro spheres.
[0234] The compounds or pharmaceutical compositions of the
disclosure can be used in combination with an amount of one or more
substances selected from anti-angiogenesis agents, signal
transduction inhibitors, antiproliferative agents, glycolysis
inhibitors, or autophagy inhibitors.
[0235] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloproteinase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase
11) inhibitors, can be used in conjunction with a compound of the
disclosure and pharmaceutical compositions described herein.
Anti-angiogenesis agents include, for example, rapamycin,
temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib,
and bevacizumab. Examples of useful COX-II inhibitors include
alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix
metalloproteinase inhibitors are described in WO 96/33172 WO
96/27583 European Patent Publication EP0818442, European Patent
Publication EP1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO
98/34915, WO 98/33768, WO 98/30566, European Patent Publication
606046, European Patent Publication 931 788, WO 90/05719, WO
99/52910, WO 99/52889, WO 99/29667, WO1999007675, European Patent
Publication EP1786785, European Patent Publication No. EP1181017,
United States Publication No. US20090012085, United States
Publication U.S. Pat. No. 5,863,949, United States Publication U.S.
Pat. No. 5,861,510, and European Patent Publication EP0780386, all
of which are incorporated herein in their entireties by reference.
Preferred MMP-2 and MMP-9 inhibitors are those that have little or
no activity inhibiting MMP-1. More preferred, are those that
selectively inhibit MMP-2 and/or AMP-9 relative to the other
matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific
examples of MMP inhibitors useful in the disclosure are AG-3340, RO
32-3555, and RS 13-0830.
[0236] The present compounds may also be used in co-therapies with
other anti-neoplastic agents, such as acemannan, aclarubicin,
aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,
aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,
ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),
bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,
cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030
(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,
dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,
doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil,
HIT diclofenac, interferon alfa, daunorubicin, doxorubicin,
tretinoin, edelfosine, edrecolomab, eflornithine, emitefur,
epirubicin, epoetin beta, etoposide phosphate, exemestane,
exisulind, fadrozole, filgrastim, finasteride, fludarabine
phosphate, formestane, fotemustine, gallium nitrate, gemcitabine,
gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination,
glycopine, goserelin, heptaplatin, human chorionic gonadotropin,
human fetal alpha fetoprotein, ibandronic acid, idarubicin,
(imiquimod, interferon alfa, interferon alfa, natural, interferon
alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1,
interferon alfa-n3, interferon alfacon-1, interferon alpha,
natural, interferon beta, interferon beta-1a, interferon beta-1b,
interferon gamma, natural interferon gamma-1a, interferon gamma-1b,
interleukin-1 beta, iobenguane, irinotecan, irsogladine,
lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan
sulfate, letrozole, leukocyte alpha interferon, leuprorelin,
levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,
lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,
miltefosine, mirimostim, mismatched double stranded RNA,
mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin,
naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,
noscapine, novel erythropoiesis stimulating protein, NSC 631570
octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel,
pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan
polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit
antithymocyte polyclonal antibody, polyethylene glycol interferon
alfa-2a, porfimer sodium, raloxifene, raltitrexed,
rasburiembodiment, rhenium Re 186 etidronate, RII retinamide,
rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim,
sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin,
tasonermin, tazarotene, tegafur, temoporfin, temozolomide,
teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin,
thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131,
trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate,
triptorelin, tumor necrosis factor alpha, natural, ubenimex,
bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine,
valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin
stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna),
ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015
(Dendreon), cetuximab, decitabine, dexaminoglutethimide,
diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,
etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,
galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),
granulocyte macrophage colony stimulating factor, histamine
dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),
interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim,
lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical
Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC
Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb
(Techniclone), polymorphic epithelial mucin-yttrium 90 MAb
(Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium,
MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant,
pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan,
satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR
Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate,
thaliblastine, thrombopoietin, tin ethyl etiopurpurin,
tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York
University), melanoma vaccine (Sloan Kettering Institute), melanoma
oncolysate vaccine (New York Medical College), viral melanoma cell
lysates vaccine (Royal Newcastle Hospital), or valspodar.
[0237] The compounds of the invention may further be used with
VEGFR inhibitors. Other compounds described in the following
patents and patent applications can be used in combination therapy:
U.S. Pat. No. 6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat.
No. 6,235,764, WO 01/32651, U.S. Pat. Nos. 6,630,500, 6,515,004,
6,713,485, 5,521,184, 5,770,599, 5,747,498, WO 02/68406, WO
02/66470, WO 02/55501, WO 04/05279, WO 04/07481, WO 04/07458, WO
04/09784, WO 02/59110, WO 99/45009, WO 00/59509, WO 99/61422, U.S.
Pat. No. 5,990,141, WO 00/12089, and WO 00/02871.
[0238] In some embodiments, the combination comprises a composition
of the present invention in combination with at least one
anti-angiogenic agent. Agents are inclusive of, but not limited to,
in vitro synthetically prepared chemical compositions, antibodies,
antigen binding regions, radionuclides, and combinations and
conjugates thereof .DELTA.n agent can be an agonist, antagonist,
allosteric modulator, toxin or, more generally, may act to inhibit
or stimulate its target (e.g., receptor or enzyme activation or
inhibition), and thereby promote cell death or arrest cell
growth.
[0239] Exemplary anti-angiogenic agents include ERBITUX.TM.
(IMC-C225), KDR (kinase domain receptor) inhibitory agents (e.g.,
antibodies and antigen binding regions that specifically bind to
the kinase domain receptor), anti-VEGF agents (e.g., antibodies or
antigen binding regions that specifically bind VEGF, or soluble
VEGF receptors or a ligand binding region thereof) such as
AVASTIN.TM. or VEGF-TRAP.TM., and anti-VEGF receptor agents (e.g.,
antibodies or antigen binding regions that specifically bind
thereto), EGFR inhibitory agents (e.g., antibodies or antigen
binding regions that specifically bind thereto) such as Vectibix
(panitumumab), IRESSA.TM. (gefitinib), TARCEVA.TM. (erlotinib),
anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen binding
regions specifically binding thereto or to their receptors, e.g.,
Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies
or antigen binding regions that specifically bind thereto). The
pharmaceutical compositions of the present invention can also
include one or more agents (e.g., antibodies, antigen binding
regions, or soluble receptors) that specifically bind and inhibit
the activity of growth factors, such as antagonists of hepatocyte
growth factor (HGF, also known as Scatter Factor), and antibodies
or antigen binding regions that specifically bind its receptor
"c-met".
[0240] Other anti-angiogenic agents include Campath, IL-8, B-FGF,
Tek antagonists (Ceretti et al., U.S. Publication No. 2003/0162712;
U.S. Pat. No. 6,413,932), anti-TWEAK agents (e.g., specifically
binding antibodies or antigen binding regions, or soluble TWEAK
receptor antagonists; see, Wiley, U.S. Pat. No. 6,727,225), ADAM
distintegrin domain to antagonize the binding of integrin to its
ligands (Fanslow et al., U.S. Publication No. 2002/0042368),
specifically binding anti-eph receptor and/or anti-ephrin
antibodies or antigen binding regions (U.S. Pat. Nos. 5,981,245;
5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent
family members thereof), and anti-PDGF-BB antagonists (e.g.,
specifically binding antibodies or antigen binding regions) as well
as antibodies or antigen binding regions specifically binding to
PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g.,
antibodies or antigen binding regions that specifically bind
thereto).
[0241] Additional anti-angiogenic/anti-tumor agents include:
SD-7784 (Pfizer, USA); cilengitide. (Merck KGaA, Germany, EPO
770622); pegaptanib octasodium, (Gilead Sciences, USA);
Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, U.S. Pat. No.
5,712,291); ilomastat, (Arriva, USA, U.S. Pat. No. 5,892,112);
emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib,
(Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA); TLC
ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA);
alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn
Mab, (Crucell, Netherlands) DAC:antiangiogenic, (ConjuChem,
Canada); Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa
Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis,
Switzerland, EP 970070); ARGENT technology, (Ariad, USA);
YIGSR-Stealth, (Johnson & Johnson, USA); fibrinogen-E fragment,
(BioActa, UK); angiogenesis inhibitor, (Trigen, UK); TBC-1635,
(Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567,
(Abbott, USA); Metastatin, (EntreMed, USA); angiogenesis inhibitor,
(Tripep, Sweden); maspin, (Sosei, Japan); 2-methoxyestradiol,
(Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA);
Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan); TAN-1120,
(Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610);
platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelial
growth factor antagonist, (Borean, Denmark); bevacizumab (pINN),
(Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); XL 784,
(Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha5beta3
integrin, second generation, (Applied Molecular Evolution, USA and
MedImmune, USA); gene therapy, retinopathy, (Oxford BioMedica, UK);
enzastaurin hydrochloride (USAN), (Lilly, USA); CEP 7055,
(Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (Genoa
Institute of Cancer Research, Italy); angiogenesis inhibitor,
(Alchemia, Australia); VEGF antagonist, (Regeneron, USA); rBPI 21
and BPI-derived antiangiogenic, (XOMA, USA); PI 88, (Progen,
Australia); cilengitide (plNN), (Merck KGaA, German; Munich
Technical University, Germany, Scripps Clinic and Research
Foundation, USA); cetuximab (INN), (Aventis, France); AVE 8062,
(Ajinomoto, Japan); AS 1404, (Cancer Research Laboratory, New
Zealand); SG 292, (Telios, USA); Endostatin, (Boston Childrens
Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (Boston
Childrens Hospital, USA); 2-methoxyestradiol, (Boston Childrens
Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene
Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935,
(AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN),
(Novartis, Switzerland and Schering AG, Germany); tissue factor
pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead
Sciences, USA); xanthorrhizol, (Yonsei University, South Korea);
vaccine, gene-based, VEGF-2, (Scripps Clinic and Research
Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University
of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN,
(EntreMed, USA); troponin I, (Harvard University, USA); SU 6668,
(SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional
Pharmaceuticals, USA); motuporamine C, (British Columbia
University, Canada); CDP 791, (Celltech Group, UK); atiprimod
(pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381,
(Harvard University, USA); AE 941, (Aeterna, Canada); vaccine,
angiogenesis, (EntreMed, USA); urokinase plasminogen activator
inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA);
HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY
RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6,
(Angstrom, USA); KR 31372, (Korea Research Institute of Chemical
Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101,
(ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA);
CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633,
(Kirin Brewery, Japan); drug delivery system, intraocular,
2-methoxyestradiol, (EntreMed, USA); anginex, (Maastricht
University, Netherlands, and Minnesota University, USA); ABT 510,
(Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI,
(ProteomTech, USA); tumor necrosis factor-alpha inhibitors,
(National Institute on Aging, USA); SU 11248, (Pfizer, USA and
SUGEN USA); ABT 518, (Abbott, USA); YH16, (Yantai Rongchang,
China); S-3APG, (Boston Childrens Hospital, USA and EntreMed, USA);
MAb, KDR, (ImClone Systems, USA); MAb, alpha5 beta1, (Protein
Design, USA); KDR kinase inhibitor, (Celltech Group, UK, and
Johnson & Johnson, USA); GFB 116, (South Florida University,
USA and Yale University, USA); CS 706, (Sankyo, Japan);
combretastatin A4 prodrug, (Arizona State University, USA);
chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany);
AGM 1470, (Harvard University, USA, Takeda, Japan, and TAP, USA);
AG 13925, (Agouron, USA); Tetrathiomolybdate, (University of
Michigan, USA); GCS 100, (Wayne State University, USA) CV 247, (Ivy
Medical, UK); CKD 732, (Chong Kun Dang, South Korea); MAb, vascular
endothelium growth factor, (Xenova, UK); irsogladine (INN), (Nippon
Shinyaku, Japan); RG 13577, (Aventis, France); WX 360, (Wilex,
Germany); squalamine (plNN), (Genaera, USA); RPI 4610, (Sirna,
USA); cancer therapy, (Marinova, Australia); heparanase inhibitors,
(InSight, Israel); KL 3106, (Kolon, South Korea); Honokiol, (Emory
University, USA); ZK CDK, (Schering AG, Germany); ZK Angio,
(Schering AG, Germany); ZK 229561, (Novartis, Switzerland, and
Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102, (Taisho,
Japan); VEGF receptor modulators, (Pharmacopeia, USA);
VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin,
(National Institutes of Health, USA); vaccine, Flk-1, (ImClone
Systems, USA); TZ 93, (Tsumura, Japan); TumStatin, (Beth Israel
Hospital, USA); truncated soluble FLT 1 (vascular endothelial
growth factor receptor 1), (Merck & Co, USA); Tie-2 ligands,
(Regeneron, USA); and, thrombospondin 1 inhibitor, (Allegheny
Health, Education and Research Foundation, USA).
[0242] Autophagy inhibitors include, but are not limited to
chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil.TM.),
bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR),
okadaic acid, autophagy-suppressive algal toxins which inhibit
protein phosphatases of type 2A or type 1, analogues of cAMP, and
drugs which elevate cAMP levels such as adenosine, LY204002,
N6-mercaptopurine riboside, and vinblastine. In addition, antisense
or siRNA that inhibits expression of proteins including but not
limited to ATG5 (which are implicated in autophagy), may also be
used.
[0243] Additional pharmaceutically active compounds/agents that can
be used in the treatment of cancers and that can be used in
combination with one or more compound of the present invention
include: epoetin alfa; darbepoetin alfa; panitumumab;
pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG
102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706, or a
pharmaceutically acceptable salt thereof.
[0244] In certain embodiments, a composition provided herein is
conjointly administered with a chemotherapeutic agent. Suitable
chemotherapeutic agents may include, natural products such as vinca
alkaloids (e.g., vinblastine, vincristine, and vinorelbine),
paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide),
antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin,
doxorubicin, and idarubicin), anthracyclines, mitoxantrone,
bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g.,
L-asparaginase which systemically metabolizes L-asparagine and
deprives cells which do not have the capacity to synthesize their
own asparagine), antiplatelet agents, antiproliferative/antimitotic
alkylating agents such as nitrogen mustards (e.g., mechlorethamine,
cyclophosphamide and analogs, melphalan, and chlorambucil),
ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and
thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05,
PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965),
alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine
(BCNU) and analogs, and streptozocin), trazenes-dacarbazinine
(DTIC), antiproliferative/antimitotic antimetabolites such as folic
acid analogs (e.g., methotrexate), pyrimidine analogs (e.g.,
fluorouracil, floxuridine, and cytarabine), purine analogs and
related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin
and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g.,
anastrozole, exemestane, and letrozole), and platinum coordination
complexes (e.g., cisplatin and carboplatin), procarbazine,
hydroxyurea, mitotane, aminoglutethimide, histone deacetylase
(HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan,
suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin,
ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus,
everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors
(e.g., Array 520), DNA binding agents (e.g., Zalypsis), PI3K delta
inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma
inhibitor (e.g., CAL-130), multi-kinase inhibitor (e.g., TG02 and
sorafenib), hormones (e.g., estrogen) and hormone agonists such as
leutinizing hormone releasing hormone (LHRH) agonists (e.g.,
goserelin, leuprolide and triptorelin), BAFF-neutralizing antibody
(e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6
(e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora
kinase inhibitors (e.g., MLN8237, AMG 900, AZD-1152), cell surface
monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1
(e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953),
PI3K/Akt inhibitors (e.g., perifosine), Akt inhibitor (e.g.,
GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g.,
Zarnestra.TM.), anti-CD138 (e.g., BT062), Torcl/2 specific kinase
inhibitor (e.g., INK128), kinase inhibitor (e.g., GS-1101), ER/UPR
targeting agent (e.g., MKC-3946), cFMS inhibitor (e.g., ARRY-382),
JAK1/2 inhibitor (e.g., CYT387), PARP inhibitor (e.g., olaparib,
Talazoparib, Niraparib veliparib (ABT-888)), BCL-2 antagonist.
Other chemotherapeutic agents may include mechlorethamine,
camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine,
navelbine, sorafenib, or any analog or derivative variant of the
foregoing.
[0245] The compounds of the present invention may also be used in
combination with radiation therapy, hormone therapy, surgery and
immunotherapy, which therapies are well known to those skilled in
the art.
[0246] In certain embodiments, a pharmaceutical composition
provided herein is conjointly administered with a steroid. Suitable
steroids may include, but are not limited to,
21-acetoxypregnenolone, alclometasone, algestone, amcinonide,
beclomethasone, betamethasone, budesonide, chloroprednisone,
clobetasol, clocortolone, cloprednol, corticosterone, cortisone,
cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,
diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort,
flucloronide, flumethasone, flunisolide, fluocinolone acetonide,
fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,
fluperolone acetate, fluprednidene acetate, fluprednisolone,
flurandrenolide, fluticasone propionate, formocortal, halcinonide,
halobetasol propionate, halometasone, hydrocortisone, loteprednol
etabonate, mazipredone, medrysone, meprednisone,
methylprednisolone, mometasone furoate, paramethasone,
prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate,
prednisolone sodium phosphate, prednisone, prednival, prednylidene,
rimexolone, tixocortol, triamcinolone, triamcinolone acetonide,
triamcinolone benetonide, triamcinolone hexacetonide, and salts
and/or derivatives thereof. In a particular embodiment, the
compounds of the present invention can also be used in combination
with additional pharmaceutically active agents that treat nausea.
Examples of agents that can be used to treat nausea include:
dronabinol; granisetron; metoclopramide; ondansetron; and
prochlorperazine; or a pharmaceutically acceptable salt
thereof.
[0247] The compounds or pharmaceutical compositions of the
disclosure can also be used in combination with an amount of one or
more substances selected from EGFR inhibitors, MEK inhibitors, PI3K
inhibitors, AKT inhibitors, TOR inhibitors, and immune therapies,
including anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and
anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.
[0248] EGFR inhibitors include, but are not limited to, small
molecule antagonists, antibody inhibitors, or specific antisense
nucleotide or siRNA. Useful antibody inhibitors of EGFR include
cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab,
nimotuzumab, and matuzumab. Small molecule antagonists of EGFR
include gefitinib, erlotinib (Tarceva), and most recently,
lapatinib (TykerB). See e.g., Yan L, et. al., Pharmacogenetics and
Pharmacogenomics In Oncology Therapeutic Antibody Development,
BioTechniques 2005; 39(4): 565-8, and Paez J G, et. al., EGFR
Mutations In Lung Cancer Correlation With Clinical Response To
Gefitinib Therapy, Science 2004; 304(5676): 1497-500.
[0249] Non-limiting examples of small molecule EGFR inhibitors
include any of the EGFR inhibitors described in the following
patent publications, and all pharmaceutically acceptable salts and
solvates of said EGFR inhibitors: European Patent Application EP
520722, published Dec. 30, 1992; European Patent Application EP
566226, published Oct. 20, 1993; PCT International Publication WO
96/33980, published Oct. 31, 1996; U.S. Pat. No. 5,747,498, issued
May 5, 1998; PCT International Publication WO 96/30347, published
Oct. 3, 1996; European Patent Application EP 787772, published Aug.
6, 1997; PCT International Publication WO 97/30034, published Aug.
21, 1997; PCT International Publication WO 97/30044, published Aug.
21, 1997; PCT International Publication WO 97/38994, published Oct.
23, 1997; PCT International Publication WO 97/49688, published Dec.
31, 1997; European Patent Application EP 837063, published Apr. 22,
1998; PCT International Publication WO 98/02434, published Jan. 22,
1998; PCT International Publication WO 97/38983, published Oct. 23,
1997; PCT International Publication WO 95/19774, published Jul. 27,
1995; PCT International Publication WO 95/19970, published Jul. 27,
1995; PCT International Publication WO 97/13771, published Apr. 17,
1997; PCT International Publication WO 98/02437, published Jan. 22,
1998; PCT International Publication WO 98/02438, published Jan. 22,
1998; PCT International Publication WO 97/32881, published Sep. 12,
1997; German Application DE 19629652, published Jan. 29, 1998; PCT
International Publication WO 98/33798, published Aug. 6, 1998; PCT
International Publication WO 97/32880, published Sep. 12, 1997; PCT
International Publication WO 97/32880 published Sep. 12, 1997;
European Patent Application EP 682027, published Nov. 15, 1995; PCT
International Publication WO 97/02266, published Jan. 23, 1997; PCT
International Publication WO 97/27199, published Jul. 31, 1997; PCT
International Publication WO 98/07726, published Feb. 26, 1998; PCT
International Publication WO 97/34895, published Sep. 25, 1997; PCT
International Publication WO 96/31510', published Oct. 10, 1996;
PCT International Publication WO 98/14449, published Apr. 9, 1998;
PCT International Publication WO 98/14450, published Apr. 9, 1998;
PCT International Publication WO 98/14451, published Apr. 9, 1998;
PCT International Publication WO 95/09847, published Apr. 13, 1995;
PCT International Publication WO 97/19065, published May 29, 1997;
PCT International Publication WO 98/17662, published Apr. 30, 1998;
U.S. Pat. No. 5,789,427, issued Aug. 4, 1998; U.S. Pat. No.
5,650,415, issued Jul. 22, 1997; U.S. Pat. No. 5,656,643, issued
Aug. 12, 1997; PCT International Publication WO 99/35146, published
Jul. 15, 1999; PCT International Publication WO 99/35132, published
Jul. 15, 1999; PCT International Publication WO 99/07701, published
Feb. 18, 1999; and PCT International Publication WO 92/20642
published Nov. 26, 1992. Additional non-limiting examples of small
molecule EGFR inhibitors include any of the EGFR inhibitors
described in Traxler, P., 1998, Exp. Opin. Ther. Patents
8(12):1599-1625.
[0250] Antibody-based EGFR inhibitors include any anti-EGFR
antibody or antibody fragment that can partially or completely
block EGFR activation by its natural ligand. Non-limiting examples
of antibody-based EGFR inhibitors include those described in
Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto,
T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin.
Cancer Res. 1:1311-1318; Huang, S. M., et al., 1999, Cancer Res.
15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res.
59:1236-1243. Thus, the EGFR inhibitor can be monoclonal antibody
Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No.
HB-8508), or an antibody or antibody fragment having the binding
specificity thereof.
[0251] MEK inhibitors include, but are not limited to, CI-1040,
AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886,
ARRY-438162, and PD-325901.
[0252] PI3K inhibitors include, but are not limited to, wortmannin,
17-hydroxywortmannin analogs described in WO 06/044453,
4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno-
[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and
described in PCT Publication Nos. WO 09/036,082 and WO 09/055,730),
2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]-
quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or
NVP-BEZ 235, and described in PCT Publication No. WO 06/122806),
(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]py-
rimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
(described in PCT Publication No. WO 2008/070740), LY294002
(2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from
Axon Medchem), PI 103 hydrochloride
(3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol
hydrochloride available from Axon Medchem), PIK 75
(N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-ni-
trobenzenesulfono-hydrazide hydrochloride available from Axon
Medchem), PIK 90
(N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicot-
inamide available from Axon Medchem), GDC-0941 bismesylate
(2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morphol-
in-4-yl-thieno[3,2-d]pyrimidine bismesylate available from Axon
Medchem), AS-252424
(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylide-
ne]-thiazolidine-2,4-dione available from Axon Medchem), and
TGX-221
(7-Methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyr-
imidin-4-one available from Axon Medchem), XL-765, and XL-147.
Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101,
PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765,
Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115,
CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.
[0253] AKT inhibitors include, but are not limited to, Akt-1-1
(inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2),
399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005)
Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al.
(2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl
compounds (e.g., WO05011700); indole-3-carbinol and derivatives
thereof (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J
Nutr. 134(12 Suppl), 3493S-3498S); perifosine (e.g., interferes
with Akt membrane localization; Dasmahapatra et al. (2004) Clin.
Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether
lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin.
Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI
identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64,
4394-9).
[0254] TOR inhibitors include, but are not limited to, inhibitors
include AP-23573, CCI-779, everolimus, RAD-001, rapamycin,
temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including
PI-103, PP242, PP30 and Torin 1. Other TOR inhibitors in FKBP12
enhancer; rapamycins and derivatives thereof, including: CCI-779
(temsirolimus), RAD001 (Everolimus; WO 9409010) and AP23573;
rapalogs, e.g. as disclosed in WO 98/02441 and WO 01/14387, e.g.
AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl)rapamycin,
40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also
called CC1779), 40-epi-(tetrazolyt)-rapamycin (also called ABT578),
32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapanycin, and other
derivatives disclosed in WO 05005434; derivatives disclosed in U.S.
Pat. No. 5,258,389, WO 94/090101, WO 92/05179, U.S. Pat. Nos.
5,118,677, 5,118,678, U.S. Pat. Nos. 5,100,883, 5,151,413,
5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO 95/14023, WO
94/02136, WO 95/16691, WO 96/41807, WO 96/41807 and U.S. Pat. No.
5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO
05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S.
Provisional Application No. 60/528,340).
[0255] Immune therapies include, but are not limited to, anti-PD-1
agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents,
and anti-OX40 agents. Exemplary anti-PD-1 antibodies and methods
for their use are described by Goldberg et al., Blood
110(1):186-192 (2007), Thompson et al., Clin. Cancer Res.
13(6):1757-1761 (2007), and Korman et al., International
Application No. PCT/JP2006/309606 (publication no. WO 2006/121168
A1), each of which are expressly incorporated by reference herein.
include: Yervoy.TM. (ipilimumab) or Tremelimumab (to CTLA-4),
galiximab (to B7.1), BMS-936558 (to PD-1), MK-3475 (to PD-1),
AMP224 (to B7DC), BMS-936559 (to B7-H1), MPDL3280A (to B7-H1),
MEDI-570 (to ICOS), AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to
LAG-3), BMS-663513 (to CD137), PF-05082566 (to CD137), CDX-1127 (to
CD27), anti-OX40 (Providence Health Services), huMAbOX40L (to
OX40L), Atacicept (to TACI), CP-870893 (to CD40), Lucatumumab (to
CD40), Dacetuzumab (to CD40), Muromonab-CD3 (to CD3), Ipilumumab
(to CTLA-4). Immune therapies also include genetically engineered
T-cells (e.g., CAR-T cells) and bispecific antibodies (e.g.,
BiTEs).
[0256] GITR agonists include, but are not limited to, GITR fusion
proteins and anti-GITR antibodies (e.g., bivalent anti-GITR
antibodies), such as, a GITR fusion protein described in U.S. Pat.
No. 6,111,090 box.c, European Patent No.: 090505B1, U.S. Pat. No.
8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or
an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962,
European Patent No.: 1947183B1, U.S. Pat. Nos. 7,812,135,
8,388,967, 8,591,886, European Patent No.: EP 1866339, PCT
Publication No.: WO 2011/028683, PCT Publication No.: WO
2013/039954, PCT Publication No.: WO2005/007190, PCT Publication
No.: WO 2007/133822, PCT Publication No.: WO2005/055808, PCT
Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720,
PCT Publication No.: WO99/20758, PCT Publication No.:
WO2006/083289, PCT Publication No.: WO 2005/115451, U.S. Pat. No.
7,618,632, and PCT Publication No.: WO 2011/051726.
[0257] The compounds described herein can be used in combination
with the agents disclosed herein or other suitable agents,
depending on the condition being treated. Hence, in some
embodiments the one or more compounds of the disclosure will be
co-administered with other agents as described above. When used in
combination therapy, the compounds described herein are
administered with the second agent simultaneously or separately.
This administration in combination can include simultaneous
administration of the two agents in the same dosage form,
simultaneous administration in separate dosage forms, and separate
administration. That is, a compound described herein and any of the
agents described above can be formulated together in the same
dosage form and administered simultaneously. Alternatively, a
compound of the disclosure and any of the agents described above
can be simultaneously administered, wherein both the agents are
present in separate formulations. In another alternative, a
compound of the present disclosure can be administered just
followed by and any of the agents described above, or vice versa.
In some embodiments of the separate administration protocol, a
compound of the disclosure and any of the agents described above
are administered a few minutes apart, or a few hours apart, or a
few days apart.
[0258] As one aspect of the present invention contemplates the
treatment of the disease/conditions with a combination of
pharmaceutically active compounds that may be administered
separately, the invention further relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of the present
invention, and a second pharmaceutical compound. The kit comprises
a container for containing the separate compositions such as a
divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes, and bags. In some embodiments,
the kit comprises directions for the use of the separate
components. The kit form is particularly advantageous when the
separate components are preferably administered in different dosage
forms (e.g., oral and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing health care
professional.
EXPERIMENTAL
[0259] Abbreviations: The following abbreviations may be used
herein: [0260] AcOH acetic acid [0261] Ac.sub.2O acetic anhydride
[0262] aq or aq. Aqueous [0263] BINAP
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [0264] DCM
Dichloromethane [0265] DEAD diethyl azodicarboxylate [0266] DMAP
4-dimethylaminopyridine [0267] DMF N,N-dimethylformamide [0268]
DMSO dimethyl sulfoxide [0269] Dppf, DPPF or dppf
1,1'-bis(diphenylphosphino)ferrocene [0270] ESI or ES electrospray
ionization [0271] Et Ethyl [0272] Et.sub.2O diethyl ether [0273]
EtOH ethyl alcohol [0274] EtOAc EtOAc [0275] G Grams [0276] H Hour
[0277] HPLC high pressure liquid chromatography [0278] IPA
isopropyl alcohol [0279] iPr Isopropyl [0280] iPr.sub.2NEt or DIPEA
N-ethyl diisopropylamine (Hunig's base) [0281] LAH lithium
aluminium hydride [0282] LC MS, LCMS, LC-MS or LC/MS liquid
chromatography mass spectroscopy [0283] LG leaving group (e.g.,
halogen, mesylate, triflate) [0284] m/z mass divided by charge
[0285] Me Methyl [0286] MeCN/CAN Acetonitrile [0287] MeOH Methanol
[0288] Met metal species for cross-coupling (e.g., MgX, ZnX,
SnR.sub.3, SiR.sub.3, B(OR).sub.2) [0289] Mg Milligrams [0290] Min
Minutes [0291] mL Milliliters [0292] MS mass spectra [0293] NMP
1-methyl-2-pyrrolidine [0294] n-BuLi n-butyllithium [0295] NMR
nuclear magnetic resonance [0296] Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) [0297]
Pd(dppf)Cl.sub.2-DCM
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [0298]
complex with dichloromethane [0299] Pd(PPh.sub.3).sub.4
tetrakis(triphenylphosphine)palladium(0) [0300] Ph.sub.3P
Triphenylphosphine [0301] PMB-NH.sub.2 4-methoxybenzylamine [0302]
Phen 1,10-phenanthroline [0303] PR or PG or Prot. group protecting
group [0304] rbf round-bottom flask [0305] RP-HPLC reverse phase
high pressure liquid chromatography [0306] RT or rt room
temperature [0307] sat. or satd. Saturated [0308] SFC supercritical
fluid chromatography [0309] TBAB tetrabutylammonium bromide [0310]
TEA or Et.sub.3N Trimethylamine [0311] TFA trifluoroacetic acid
[0312] THF Tetrahydrofuran [0313] Xantphos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
[0314] Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. All
parts are by weight and temperatures are in degrees centigrade
unless otherwise indicated. All microwave assisted reactions were
conducted with a Smith Synthesizer.TM. from Biotage.TM.. All
compounds showed NMR spectra consistent with their assigned
structures. Melting points were determined on a Buchi apparatus and
are uncorrected. Mass spectral data was determined by electrospray
ionization technique. All examples were purified to >9000 purity
as determined by high-performance liquid chromatography. Unless
otherwise stated, reactions were run at room temperature.
[0315] In synthesizing compounds of the present invention, it may
be desirable to use certain leaving groups. The term "leaving
groups" ("LG") generally refer to groups that are displaceable by a
nucleophile. Such leaving groups are known in the art. Examples of
leaving groups include, but are not limited to, halides (e.g., I,
Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g.,
SCH.sub.3), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the
like. Examples of nucleophiles include, but are not limited to,
amines, thiols, alcohols, Grignard reagents, anionic species (e.g.,
alkoxides, amides, carbanions) and the like.
[0316] The examples presented below illustrate specific embodiments
of the present invention. These examples are meant to be
representative and are not intended to limit the scope of the
claims in any manner.
[0317] It is noted that when a percent (%) is used with regard to a
liquid, it is a percent by volume with respect to the solution.
When used with a solid, it is the percent with regard to the solid
composition. Materials obtained from commercial suppliers were
typically used without further purification. Reactions involving
air or moisture sensitive reagents were typically performed under a
nitrogen or argon atmosphere. Purity was measured using high
performance liquid chromatography (HPLC) system with UV detection
at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8
4.6.times.150 mm, 5 .mu.m, 5 to 100% CH.sub.3CN in H.sub.2O with
0.1% TFA for 15 min at 1.5 mL/min; System B: Zorbax SB-C8,
4.6.times.75 mm, 10 to 90% CH.sub.3CN in H.sub.2O with 0.1% formic
acid for 12 min at 1.0 mL/min) (Agilent Technologies, Santa Clara,
Calif.). Silica gel chromatography was generally performed with
prepacked silica gel cartridges (Biotage, Uppsala, Sweden or
Teledyne-Isco, Lincoln, Nebr.). .sup.1H NMR spectra were recorded
on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation,
Madison, Wis.) or a Varian (Agilent Technologies, Santa Clara,
Calif.) 400 MHz spectrometer at ambient temperature. All observed
protons are reported as parts per million (ppm) downfield from
tetramethylsilane (TMS) or other internal reference in the
appropriate solvent indicated. Data are reported as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,
q=quartet, br=broad, m=multiplet), coupling constants, and number
of protons. Low-resolution mass spectral (MS) data were determined
on an Agilent 1100 Series (Agilent Technologies, Santa Clara,
Calif.) LC/MS with UV detection at 254 nm and 215 nm and a low
resonance electrospray mode (ESI).
General Synthetic Scheme
[0318] Unless otherwise stated, starting materials and reagents
used in preparing these compounds are either available from
commercial suppliers such as Aldrich Chemical Co., (Milwaukee,
Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are
prepared by methods known to those skilled in the art following
procedures set forth in references such as Fieser and Fieser's
Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,
1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and
Supplementals (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989). These schemes are merely illustrative of some methods
by which the compounds of this invention can be synthesized, and
various modifications to these schemes can be made and will be
suggested to one skilled in the art having referred to this
disclosure. The starting materials and the intermediates, and the
final products of the reaction may be isolated and purified if
desired using conventional techniques, including but not limited to
filtration, distillation, crystallization, chromatography and the
like. Such materials may be characterized using conventional means,
including physical constants and spectral data.
[0319] Unless specified to the contrary, the reactions described
herein take place at atmospheric pressure over a temperature range
from about -78.degree. C. to about 150.degree. C., more preferably
from about 0.degree. C. to about 125.degree. C. and most preferably
at about room (or ambient) temperature, e.g., about 20.degree.
C.
[0320] For the purpose of clarity in this general synthesis
section, Compounds of Formula (I) as defined in the summary of the
inventions can be schematically drawn to contain Ring Ar.sup.1 and
Ar.sup.2 as follows:
##STR00041##
[0321] wherein the group L is --NR.sup.3, --O--, --S--, S.dbd.O, or
S(.dbd.O).sub.2; X.sup.1 is N or --CR.sup.6, X.sup.2 is N or
--CR.sup.3a, X.sup.3 is N or --CR.sup.3a, X.sup.4 is N or
--CR.sup.3c, X.sup.5 is N or --CR.sup.3d, X.sup.6 is N or
--CR.sup.3e and X.sup.7 is N or --CR.sup.3f; Ring Ar.sup.1 is
located to the left of the linker, and ring Ar.sup.2 is located to
the right of linker, fused to the ring containing the groups
X.sup.3; X.sup.4; and X.sup.5.
[0322] Generally, compounds of Formula (I), can be synthesized via
three general steps as follows:
[0323] Step 1: Preparation of Ring Ar.sup.1 compound.
[0324] Step 2: Preparation of Ring Ar.sup.2 compound.
[0325] Step 3: Combination of Ring Ar.sup.1 compound to Ring
Ar.sup.2 compound.
[0326] The generic Schemes A-C below are meant to provide guidance
to the ordinarily skilled synthetic chemist, who will readily
appreciate that the solvent, concentration, reagent, protecting
group, order of synthetic steps, time, temperature, and the like
can be modified as necessary, well within the skill and judgment of
the ordinarily skilled artisan.
[0327] In one embodiment, Schemes A-B below provide generic
preparation of a compound of Formula (I); having the following
formula:
##STR00042##
which embodies compounds of formulae (Ia), (Ib), (Ic), and (Id) as
described herein:
##STR00043##
[0328] Scheme A: Preparation of Compounds (Ia), (Ib), (Ic), and
(Id):
[0329] According to Scheme A, in one embodiment, a compound of
Formulae (Ia), (Ib), (Ic), and (Id) as disclosed herein can be
synthesized as follows:
Step A-1-a: Preparation of Ring Ar.sup.1 Compounds Wherein X.sup.1
is N or --CR.sup.6 and X.sup.2 is N or --CR.sup.3a
##STR00044##
[0331] Compound A-1, wherein W.sup.1 is a halogen, for example
fluoro, chloro, bromo can be reacted with an R.sup.2 group
containing agent via metal catalyzed amination, where a suitable
palladium or copper catalyst and a base are used, in the presence
of a suitable base, in a suitable organic solvent such as NMP,
dioxane, acetonitrile, tetrahydrofuran, DMF, toluene, and the like.
Compound A-1 is commercially available or can be synthesized by
known methods by those skilled in the art. Examples of compound A-1
include, but are not limited to, 1-bromo-3-methyl-5-nitrobenzene or
1-bromo-5-nitrobenzene. Examples of R.sup.2 reagents include, but
not limited to (1) (R)-2-methylmorpholine, (2)
4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine
hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5)
2-aminoethan-1-ol, or (6) 2-amino 3-methylpropan-1-ol. Examples of
bases include, but are not limited to diisopropylethyl amine,
potassium carbonate, or sodium tert-butoxide. This step is followed
by a reduction with a suitable palladium catalyst and a hydrogen
source, such as Pd/C in the presence of hydrogen gas, or reduction
in the presence of iron to form compound A-2.
Step A-1-b: Preparation of Ring Ar.sup.1 Compound Wherein X.sup.1
is N or --CR.sup.6 and X.sup.2 is N
##STR00045##
[0333] Compound A-3, wherein W.sup.1 is a halogen, for example
fluoro, chloro, bromo can be reacted with an R.sup.2 group
containing agent in the presence of a suitable base, in a suitable
organic solvent such as NMP, dioxane, acetonitrile,
tetrahydrofuran, DMF, and the like to form compound A-4. Compound
A-3 is commercially available or can be synthesized by known
methods by those skilled in the art. Examples of compound A-3
include, but are not limited to, 6-fluoropyridin-2-amine,
2-chloro-6-methylpyrimidin-4-amine or
2-chloro-6-methylpyridin-4-amine. Examples of R.sup.2 reagents
include, but not limited to (1) (R)-2-methylmorpholine, (2)
4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine
hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5)
2-aminoethan-1-ol, (6) 2-amino3-methylpropan-1-ol, or (7)
3,3,3-trifluoropropan-1-ol. Examples of bases include, but are not
limited to diisopropylethyl amine, potassium carbonate, or sodium
hydride.
Step A-1-c: Preparation of Ring Ar.sup.1 Compound Wherein X.sup.1
is --CR.sup.6 and X.sup.2 is N or --CR.sup.3a
##STR00046##
[0335] Alternatively, compound A-5, wherein W.sup.1 is a halogen,
for example chloro, bromo, or iodo can be reacted with an R.sup.2
group having a formula of R.sup.13--NH containing agent via metal
catalyzed amination, where a suitable palladium or copper catalyst
and a base are used, in the presence of a suitable base, in a
suitable organic solvent such as NMP, dioxane, acetonitrile,
tetrahydrofuran, DMF, DMSO, and the like to form compound A-6.
Compound A-5 is commercially available or can be synthesized by
known methods by those skilled in the art. Examples of compound A-5
include, but are not limited to, 3-bromo-5-methylphenol,
3-bromophenol, 3-bromo-4-methylphenol Examples of R.sup.2 reagents
include, but is not limited to (1) (R)-2-methylmorpholine, (2)
4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine
hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5)
2-aminoethan-1-ol, or (6) 2-amino3-methylpropan-1-ol.
[0336] Examples of bases include, but are not limited to
diisopropylethyl amine, potassium carbonate, cesium carbonate, or
sodium tert-butoxide.
Step A-2: Preparation of Ar.sup.2 Compound
##STR00047##
[0338] In Step A-2, Compound A-7, wherein each of W.sup.1, W.sup.2,
and W.sup.3 is independently a halogen, for example fluoro, chloro,
bromo, or iodo, can be reacted with an R.sup.X reagent, such as (1)
6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine
hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4)
4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5)
7-azaspiro[3.5]nonane hydrochloride, in a suitable organic solvent
such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene
chloride, DMSO, and the like, to form Compound A-8, which is then
treated with a protected amine compound, such as PMB protected
amine compound, in the presence of a base, such as diisopropylethyl
amine or triethyl amine, in a suitable organic solvent to give
compound A-9. Compound A-9 is then reacted with a deprotecting
agent, such as trifluoroacetic acid, to give compound A-10.
Step A-3-a: Coupling of Ring Ar.sup.1 Compound to Ring Ar.sup.2
Compound Followed by Introduction of R.sup.1 to Form Compounds (Ia)
or (Ib)
##STR00048##
[0340] In Step A-3, compound A-10, which was obtained from Step
A-2, can be reacted with an orthoformate reagent having formula
CR.sup.3c(OR).sub.3, wherein R.sup.3c is H or methyl, such as
triethyl orthoformate in acetic anhydride to form compound A-11,
which can be reacted with compound A-2 in the presence of acetic
acid to form compound A-12. Those ordinary skilled synthetic
chemists will readily understand that other cyclization agents can
be used. Further manipulation of halogen group W.sup.3 by
transformation reactions such as, metal-catalyzed sulfoamidation,
sulfination, or sulfonylation, in a suitable organic solvent such
as DMSO, acetonitrile, tetrahydrofuran, DMF, methylene chloride,
and the like, in the presence of a metal catalyst and an R.sup.1
reagent, such as (1) 1-methylcyclopropane-1-sulfonamide, (2)
3-methyloxetan-3-amine, (3) tert-butyl
3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate,
(5) 2-hydroxypropane-1-sulfonamide, (6)
2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8)
2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10)
2-aminoethan-1-ol, or (11) cyclopropanethiol can be used to form
Compound (Ia) or (Ic). Those ordinary skilled in the art will
readily understand that coupling reaction such as shown in Step
A-3-a can be performed under various known conditions.
Step A-3-b: Coupling of Ring Ar.sup.1 Compound to Ring Ar.sup.2
Compound Followed by Introduction of R.sup.1 to Form Compounds (Ic)
or (Id)
##STR00049##
[0342] Alternatively, Compound A-10 can be treated with formic acid
at high temperature, ranging from 100.degree. C. to 120.degree. C.,
followed by chlorination reaction with a chlorinating agent, such
as POCl.sub.3, in organic solvent, such as toluene to form compound
A-14, wherein R.sup.3c is H. Compound A-14 can then be treated with
compound A-4 according to a similar procedure as described above in
Step A-3-a to give Compound (Ic) or (Id).
[0343] Scheme B: Preparation of Compound (Ie):
[0344] In another embodiment, Scheme B provides generic preparation
of a compound of Formula (I): having the following formula:
##STR00050##
which embodies compounds of formulae (Ie) as described herein:
##STR00051##
Step B-1: Preparation of Ring Ar.sup.1 Compound
[0345] Ring Ar.sup.1 compound of Compound (Ie) can be prepared
according to the process described in Steps A-1-a to A-1-c of
SCHEME A above.
Step B-2: Preparation of Ring Ar.sup.2 Compound
##STR00052##
[0347] In Step B-2, Compound B-1, wherein each of W.sup.4 and
W.sup.5 is independently halo, for example fluoro, chloro, bromo,
or iodo, can be reacted with an R.sup.X reagent, such as (1)
6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine
hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4)
4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5)
7-azaspiro[3.5]nonane hydrochloride, in a suitable organic solvent
such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene
chloride, DMSO, and the like, to form Compound B-2, which is then
treated with oxalyl chloride followed by diethyl amine to form the
diethyl amide derivative B-3. Compound B-3 is then treated with
nBuLi and DMF the aromatic aldehyde derivative B-4, which is then
reacted with a cyclization agent, such as hydrazine, followed by
chlorination with POCl.sub.3 to give compound B-5.
Step B-3: Coupling of Ring Ar.sup.1 Compound to Ring Ar.sup.2
Compound Followed by Introduction of R.sup.1 to Form Compounds
(Ie)
##STR00053##
[0349] In step B-3 compound B-5 can be treated with compound A-4
according to analogous procedure and condition as described above
in Step A-3-a to give Compound (Ie).
[0350] Preparation of Synthetic Intermediates
[0351] Preparation of Ring Ar.sup.1 Intermediates
Intermediate 1: 3-(4,4-Difluoropiperidin-1-yl)-5-methylaniline
##STR00054##
[0353] Step 1: To a solution of 1-bromo-3-methyl-5-nitrobenzene (10
g, 46.3 mmol) and 4,4-difluoropiperidine hydrochloride (10.9 g,
69.4 mmol) in toluene (50 mL), was added sodium tert-butoxide (13.3
g, 139 mmol), Pd.sub.2(dba).sub.3 (4.24 g, 4.63 mmol) and xantphos
(2.68 g, 4.63 mmol). The reaction mixture was heated at 100.degree.
C. for 1.5 h and allowed to cool to room temperature. The reaction
mixture was diluted with water, passed through a bed of
CELITE.RTM., and washed with EtOAc. The organic extracts were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography eluting with 10% to 20% EtOAc in petroleum
ether to provide 4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine
(2.3 g, 9.0 mmol, 19% yield) as a grey solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 7.55 (t, J=2.3 Hz, 1H), 7.45 (s, 1H),
7.32 (d, J=2.3 Hz, 1H), 3.46 (t, J=5.8 Hz, 4H), 2.38 (s, 3H), 2.05
(tt, J=14.1, 5.8 Hz, 4H).
[0354] Step 2: To a solution of
4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine (2.3 g, 9.0 mmol)
in EtOH (23 mL) and water (4.6 mL) were added iron powder (5.01 g,
90 mmol) and ammonium chloride (4.80 g, 90 mmol) at rt and then
heated at 80.degree. C. for 16 h. The reaction mixture was cooled
to rt, filtered through a CELITE.RTM. pad, and washed with MeOH.
The filtrate was evaporated to dryness and purified by flash column
chromatography eluting with 30% to 40% EtOAc in petroleum ether to
provide 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (1.8 g, 8.0
mmol, 89% yield) as a brown solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 6.00 (d, J=1.7 Hz, 2H), 5.89 (q, J=1.4
Hz, 1H), 4.81 (s, 2H), 3.20 (d, J=11.5 Hz, 4H), 2.09 (s, 3H),
1.94-2.04 (m, 4H). m/z (ESI): 227.2 (M+H).sup.+.
Intermediate 2: 3-Methyl-5-(3,3,3-trifluoropropoxy)aniline
##STR00055##
[0356] Step 1: To a solution of 3-methyl-5-nitrophenol (2.0 g, 13.1
mmol) and 3,3,3-trifluoropropan-1-ol (6.0 g, 52.2 mmol) in THF (30
mL) was added PPh.sub.3 (13.70 g, 52.2 mmol) followed by diethyl
(E)-diazene-1,2-dicarboxylate (8.27 mL, 52.2 mmol) at 0.degree. C.
The reaction mixture was stirred at rt for 3 h before it was
diluted with water and extracted with EtOAc. The organic extracts
were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to give the crude material as an orange oil.
Purification by flash column chromatography eluting with a gradient
of 0% to 20% EtOAc in petroleum ether provided
1-methyl-3-nitro-5-(3,3,3-trifluoropropoxy)benzene (2.3 g, 8.8
mmol, 67% yield) as yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.63-7.66 (m, 1H), 7.51 (t, J=2.4 Hz, 1H), 7.24 (dt,
J=2.4, 0.9 Hz, 1H), 4.29 (t, J=5.8 Hz, 2H), 2.79 (m, 2H), 2.37-2.41
(s, 3H).
[0357] Step 2: To a solution of
1-methyl-3-nitro-5-(3,3,3-trifluoropropoxy)benzene (1.3 g, 5.22
mmol) in EtOH (20 mL) and water (2 mL) were added ammonium chloride
(1.67 g, 31.3 mmol), iron powder (1.75 g, 31.3 mmol) and HCl (12 N,
2.0 mL, 5.22 mmol). The reaction mixture was heated at 80.degree.
C. for 4 h before it was filtered through a CELITE.RTM. pad and
washed with EtOAc. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give
the crude material as orange oil. The crude material was purified
by flash column chromatography eluting with 5% to 50% EtOAc in
petroleum ether to provide
3-methyl-5-(3,3,3-trifluoropropoxy)aniline (0.6 g, 2.7 mmol, 52%
yield) as a brown oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
ppm 6.01 (q, J=1.3 Hz, 1H), 5.96 (t, J=2.2 Hz, 1H), 5.93 (t, J=2.0
Hz, 1H), 4.05 (t, J=5.9 Hz, 2H), 2.69 (qt, J=11.5, 5.9 Hz, 2H),
2.10 (s, 3H). m/z (ESI): 220.1 (M+H).sup.+.
Intermediate 3: 6-(3,3,3-Trifluoropropoxy)pyridin-2-amine
##STR00056##
[0359] A mixture of 6-fluoropyridin-2-amine (1.00 g, 8.92 mmol) and
3,3,3-trifluoropropan-1-ol (2.03 g, 17.84 mmol) in dioxane (15 mL)
was treated with NaH (0.86 g, 35.7 mmol) at 0.degree. C. under
nitrogen atmosphere and then heated at 90.degree. C. for 2 h. The
reaction mixture was quenched with cold water and extracted with
EtOAc. The organic extract was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
material was purified by flash column chromatography eluting with
10% to 20% EtOAc in petroleum ether to provide the title compound
(1.30 g, 6.31 mmol, 71% yield) as a light-yellow oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 7.29 (t, J=7.8 Hz, 1H), 6.01
(dd, J=7.8, 0.7 Hz, 1H), 5.80-5.91 (m, 3H), 4.34 (t, J=6.2 Hz, 2H),
2.74 (dtd, J=17.7, 11.6, 6.2 Hz, 2H). m/z (ESI): 207.2
(M+H).sup.+.
Intermediate 4:
2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine
##STR00057##
[0361] A mixture of 2-chloro-6-methylpyrimidin-4-amine (46 g, 320
mmol, Combi-Blocks, San Diego, Calif.), 4,4-difluoropiperidine
hydrochloride (76 g, 481 mmol, Combi-Blocks, San Diego, Calif.) and
DIPEA (166 mL, 961 mmol) in NMP (460 mL, 10.00 mL/g) was taken in
an autoclave (1 L) and heated at 180.degree. C. for 30 h. The
reaction mixture was cooled to room temperature and quenched with
water (500 mL), extracted with EtOAc (2.times.1000 mL). The organic
layer was washed with brine (500 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The crude
material was adsorbed onto a plug of silica gel and purified by
column chromatography over silica gel, eluting with 50% to 100%
EtOAc in hexanes. The product was re-dissolved in EtOAc (500 mL)
and washed with water (2.times.500 mL). The organic layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The yellow solid was once again suspended in hexanes (400
mL) and stirred for 30 min. The slurry was filtered, washed with
hexanes (100 mL), dried under vacuum to provide the title compound
(58 g, 79% yield) as a pale-yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80-3.78
(dd, J=6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95-1.85 (tt, J=14.2, 5.7
Hz, 4H). m/z (ESI): 229.2 (M+H).sup.+.
Intermediate 5:
2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-amine
##STR00058##
[0363] A mixture of 2-bromo-6-methylpyridin-4-amine (1.70 g, 9.09
mmol) and 4,4-difluoropiperidine hydrochloride (2.86 g, 18.18 mmol)
in NMP (10 mL) was heated at 180.degree. C. for 10 h. The reaction
mixture was diluted with H.sub.2O and extracted with EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and concentrated under reduced pressure. The crude material was
purified by SFC [method: Greensep Silica (250.times.30 mm, 5
.mu.m), 70:30 (Liquid CO.sub.2:20 mM NH.sub.3 in MeOH)] to provide
2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-amine (1.00 g,
4.40 mmol, 49% yield) as a brown oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 5.85 (s, 1H), 5.79-5.91 (m, 3H),
3.45-3.59 (m, 4H), 2.13 (s, 3H), 1.90-2.01 (m, 4H). m/z (ESI):
228.2 (M+H).sup.+.
Intermediate 6:
6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2-amine
##STR00059##
[0365] Step 1: In an autoclave (3 L) were added
2,6-dichloro-4-methylpyridine (80 g, 490 mmol),
4,4-difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA
(342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was
heated at 180.degree. C. for 24 h. The reaction mixture was cooled
to room temperature and basified to pH-9 using 10% aq. NaHCO.sub.3
solution. The reaction mixture was extracted with EtOAc
(2.times.1500 mL), washed with water (1500 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude material was purified by column chromatography
over silica gel (60-120 mesh) using 5-10% EtOAc in hexanes to give
the mixture of 2,6-dichloro-4-methylpyridine and
2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine in 1:3
ratio (102 g) as a pale brown oil. This mixture (102 g) was further
purified by reverse phase chromatography using 60%
CH.sub.3CN/H.sub.2O as an eluent to give
2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58%
yield) as a pale brown liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 6.76 (s, 1H), 6.57 (s, 1H), 3.66 (t, J=5.6 Hz, 4H), 2.22
(s, 3H), 2.03-1.91 (m, 4H). m/z (ESI): 247.1 (M+H).sup.+.
[0366] Step 2: To a solution of
2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (30.0 g,
122 mmol) in 1,4-dioxane (300 mL) were added
(4-methoxyphenyl)methanamine (23.8 mL, 182 mmol) and
Cs.sub.2CO.sub.3 (79 g, 240 mmol). The reaction mixture was
degassed and purged with nitrogen for 30 min. BINAP (7.57 g, 12.2
mmol) and Pd(OAc).sub.2 (2.73 g, 12.2 mmol) were added and the
reaction mixture was stirred at 100.degree. C. for 16 h. The
reaction mixture was cooled to room temperature, filtered through a
CELITE.RTM. bed, and washed with EtOAc (100 mL). The filtrate was
concentrated under reduced pressure. The residue was extracted with
EtOAc (2.times.500 mL), washed with water (500 mL) followed by
brine (500 mL). The organic layer was dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The crude
residue was purified by column chromatography over silica gel using
5-8% EtOAc in hexanes to give
6-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amin-
e (48 g, 76% yield) as a yellow oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.22 (d, J=7.2 Hz, 2H), 6.85 (d, J=7.2 Hz,
2H), 6.64 (t, J=6.0 Hz, 1H), 5.84 (s, 1H), 5.68 (s, 1H), 4.31 (d,
J=6.0 Hz, 2H), 3.71 (s, 3H), 3.56 (t, J=5.6 Hz, 4H), 2.05 (s, 3H),
1.90-1.80 (m, 4H). m/z (ESI): 348.1 (M+H).sup.+.
[0367] Step 3: To a solution of
6-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amin-
e (48.0 g, 138 mmol) in dry DCM (480 mL) were added anisole (30.2
mL, 276 mmol) and TFA (240 mL, 3120 mmol). The reaction mixture was
stirred at 55.degree. C. for 4 h and concentrated under reduced
pressure. The residue was dissolved in water (200 mL) and basified
with 10% aq. sodium bicarbonate solution to pH-8 and extracted with
EtOAc (2.times.500 mL). The combined organic layers were washed
with water (200 mL) followed by brine (200 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The crude residue was purified by column chromatography
over silica gel using 25% to 35% EtOAc in hexanes to give
6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine as a brown
oil. This material was further purified by reverse phase
chromatography using 50-60% CH.sub.3CN/H.sub.2O to give
6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (16.5 g, 72
mmol, 53% yield) as a brown oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 5.86 (s, 1H), 5.65 (s, 1H), 5.48 (s, 2H),
3.56 (t, J=5.2 Hz, 4H), 2.06 (s, 3H), 1.96-1.87 (m, 4H). m/z (ESI):
228.2 (M+H).sup.+.
Intermediate 7: 3-(4,4-Difluoropiperidin-1-yl)-5-methylphenol
##STR00060##
[0369] A mixture of 3-bromo-5-methylphenol (1.00 g, 5.35 mmol),
4,4-difluoropiperidine hydrochloride (1.26 g, 8.02 mmol),
K.sub.2CO.sub.3 (1.48 g, 10.69 mmol), copper(I) iodide (0.20 g,
1.07 mmol) and L-proline (0.25 g, 2.14 mmol) in DMSO (10 mL) was
heated at 65.degree. C. for 16 h. The reaction mixture was filtered
through a CELITE.RTM. bed and washed with EtOAc. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude material was purified by flash
column chromatography eluting with 0% to 15% EtOAc in petroleum
ether to provide 3-(4,4-difluoropiperidin-1-yl)-5-methylphenol
(0.20 g, 0.88 mmol, 16% yield) as a brown oil. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 9.06 (s, 1H), 6.26 (t, J=2.0 Hz,
1H), 6.16 (t, J=2.3 Hz, 1H), 5.95-6.11 (m, 1H), 3.12-3.28 (m, 4H),
2.15 (s, 3H), 1.85-2.09 (m, 4H). m/z (ESI): 228.3 (M+H).sup.+.
[0370] Preparation of Ring Ar.sup.2 Intermediates
Intermediate 8:
2-Amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
##STR00061##
[0372] Step 1: A solution of 4-bromo-2,6-difluorobenzonitrile (10
g, 46 mmol) and DIPEA (16 mL, 92 mmol) in DMSO (100 mL) was cooled
to 0.degree. C. and then treated with 6-azaspiro[2.5]octane (4.1 g,
36.7 mmol). The reaction mixture was stirred at rt for 16 h before
it was diluted with water and extracted with EtOAc. The organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude product was purified
by reverse-phase preparative HPLC (0.1% TFA in CH.sub.3CN/H.sub.2O)
to provide
4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (12 g,
39 mmol, 85% yield) as an off-white solid. .sup.1H NMR (400 MHz,
Chloroform-d): .delta. ppm 6.93 (t, J=1.4 Hz, 1H), 6.88 (dd, J=8.1,
1.6 Hz, 1H), 3.31-3.40 (m, 4H), 1.59 (d, J=1.5 Hz, 4H), 0.40 (s,
4H). m/z (ESI): 309.2 (M)+.
[0373] Step 2: To a solution of
4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.0 g,
3.2 mmol) and DIPEA (1.13 mL, 6.47 mmol) in NMP (8 mL) was added
(2,4-dimethoxyphenyl)methanamine (0.52 g, 3.10 mmol) at rt and the
resulting solution was heated at 120.degree. C. for 16 h. The
reaction mixture was diluted with water and extracted with EtOAc.
The organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
product was purified by flash column chromatography using a
gradient of 10% to 60% EtOAc in petroleum ether to afford
4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-y-
l)benzonitrile (1.05 g, 2.30 mmol, 71% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 7.11 (d, J=8.4 Hz,
1H), 6.52-6.61 (m, 2H), 6.49 (dd, J=8.4, 2.4 Hz, 1H), 6.35-6.42 (m,
2H), 4.26 (d, J=6.0 Hz, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.10 (t,
J=5.3 Hz, 4H), 1.47 (t, J=5.2 Hz, 4H), 0.33 (s, 4H). m/z (ESI):
456.1/458.1 (M+H).sup.+.
[0374] Step 3: A solution of
4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzo-
nitrile (1.0 g, 2.2 mmol) and anisole (0.60 mL, 5.48 mmol) in TFA
(5 mL) was stirred at rt for 16 h. Then the reaction mixture was
quenched with a satd. aq. NaHCO.sub.3 and extracted with EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography using, 20%
EtOAc in petroleum ether, to afford
2-amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.61 g,
1.99 mmol, 91% yield) as a pale-yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 6.87-7.01 (s, 2H), 6.42 (s, 1H), 6.32
(d, J=1.8 Hz, 1H), 3.04-3.11 (m, 4H), 1.47 (t, J=5.3 Hz, 4H), 0.33
(s, 4H). m/z (ESI): 306.0/308.0 (M+H).sup.+.
Intermediate 9: Ethyl
(E)-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate
##STR00062##
[0376] A solution of
2-amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.4 g,
1.3 mmol, Intermediate 8) in triethyl orthoformate (5 mL, 30 mmol)
was treated with Ac.sub.2O (0.1 mL, 1.1 mmol) at rt and then heated
at 145.degree. C. for 16 h. Then the reaction mixture was
concentrated under reduced pressure and ice-cold water was added to
get a solid, which was filtered, to provide the title compound (0.4
g, 1.1 mmol, 85% yield) as a brown solid. The compound was directly
taken without further purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 8.11 (s, 1H), 6.88-7.14 (m, 2H), 4.29
(q, J=7.1 Hz, 2H), 3.64-3.83 (m, 4H), 1.49 (t, J=5.3 Hz, 4H), 1.33
(t, J=7.1 Hz, 3H), 0.35 (s, 4H). m/z (ESI): 362.0/364.0
(M).sup.+.
TABLE-US-00002 TABLE 1 Intermediate 9-1 was prepared analogous to
preparation of Intermediate 9: LRMS: (ESI + Ex. ve ion) # Chemical
Structure Name m/z 9-1 ##STR00063## Methyl (E)-N- (5-bromo-2-
cyano-3-(6- azaspiro[2.5] octan-6-yl) phenyl) acetimidate 363.1
Intermediate 10:
2-Amino-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
##STR00064##
[0378] Step 1: To a solution of
4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (2.1 g,
6.8 mmol) in DMSO (1.6 mL) were added tetrabutylammonium bromide
(2.41 g, 7.47 mmol), 1,10-phenanthroline (0.184 g, 1.019 mmol),
palladium(II) acetate (0.076 g, 0.340 mmol), triphenylphosphine
(0.267 g, 1.019 mmol), sodium formate (1.02 g, 14.94 mmol), and
di-potassium disulphite (3.02 g, 13.58 mmol) at rt and was heated
at 70.degree. C. for 2 h. The reaction mixture was cooled to rt and
then iodomethane (0.64 mL, 10.19 mmol) was added to it and stirred
for 16 h at rt. The resultant reaction mixture was filtered through
a CELITE.RTM. pad and washed with EtOAc. The organic layer was
washed with brine, filtered, and concentrated to get the crude
material which was purified by flash column chromatography eluting
with a gradient of 20% to 25% EtOAc in petroleum ether to provide
2-fluoro-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
(0.68 g, 2.21 mmol, 32% yield) as an off-white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 7.36-7.46 (m, 2H), 3.37-3.46
(m, 4H), 3.34 (s, 3H), 1.49-1.56 (m, 4H), 0.39 (s, 4H). m/z (ESI):
309.1 (M+H).sup.+.
[0379] Step 2: To a mixture of
2-fluoro-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
(0.65 g, 2.11 mmol) and DIPEA (1.11 mL, 6.32 mmol) in NMP (6.5 mL)
was added (2,4-dimethoxyphenyl)methanamine (0.38 g, 2.27 mmol) at
rt and then heated at 125.degree. C. for 18 h. The reaction mixture
was diluted with water and extracted with EtOAc. The organic layer
was washed with brine, filtered, and concentrated to get the crude
material which was purified by flash column chromatography eluting
with a gradient of 0% to 20% EtOAc in petroleum ether to provide
2-((2,4-dimethoxybenzyl)amino)-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-
-6-yl)benzonitrile (0.68 .mu.g, 1.49 mmol, 71% yield) as a
pale-yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
7.14 (d, J=8.4 Hz, 1H), 6.85 (t, J=6.1 Hz, 1H), 6.69 (dd, J=17.5,
1.5 Hz, 2H), 6.57 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.4, 2.4 Hz, 1H),
4.34 (d, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.20-3.18 (m,
4H), 2.70 (s, 3H), 1.50 (t, J=5.3 Hz, 4H), 0.36 (s, 4H). m/z (ESI):
456.1 (M+H).sup.+.
[0380] Step 3: To a solution of
2-((2,4-dimethoxybenzyl)amino)-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-
-6-yl)benzonitrile (0.66 g, 1.45 mmol) in TFA (3.3 mL, 42.8 mmol)
was added anisole (0.37 mL, 3.62 mmol) at rt and stirred for 6 h.
The reaction mixture was evaporated to dryness, quenched with satd.
NaHCO.sub.3 solution, and extracted with EtOAc. The organic layer
was dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum. The crude product was purified by flash column
chromatography using 20% EtOAc in petroleum ether to afford
2-amino-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
(0.41 g, 1.31 mmol, 90% yield) as a pale-yellow solid. .sup.1H NMR
(400 MHz, DMSO-d6): .delta. ppm 6.89 (d, J=1.5 Hz, 1H), 6.60 (d,
J=1.6 Hz, 1H), 6.49 (s, 2H), 3.18 (d, J=7.4 Hz, 7H), 1.50 (t, J=5.3
Hz, 4H), 0.35 (s, 4H). m/z (ESI): 306.0 (M+H).sup.+.
Intermediate 11:
2-Amino-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
##STR00065##
[0382] Step 1: To a solution of 2,6-difluorobenzonitrile (2.0 g,
14.4 mmol) in DMSO (50 mL) was added DIPEA (5.0 mL, 28.8 mmol) and
6-azaspiro[2.5]octane (1.28 g, 11.50 mmol) at 0.degree. C. and then
stirred at rt for 16 h. The reaction mixture was diluted with water
and extracted in EtOAc. The organic extract was washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The crude material was purified by flash column chromatography
eluting with a gradient of 0% to 5% EtOAc in petroleum ether to
provide 2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.86 g,
8.08 mmol, 56% yield) as a colorless sticky liquid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 7.60 (td, J=8.4, 7.1 Hz, 1H),
6.91-7.03 (m, 2H), 3.22-3.30 (m, 4H), 1.47-1.54 (m, 4H), 0.36 (s,
4H). m/z (ESI): 231.2 (M+H).sup.+.
[0383] Step 2: To a solution of
2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.81 g, 7.82
mmol) in NMP (20 mL) were added DIPEA (4.10 mL, 23.45 mmol) and
(2,4-dimethoxyphenyl)methanamine (1.44 g, 8.60 mmol) at rt and then
heated at 145.degree. C. for 30 h. The reaction mixture was diluted
with ice cold water and extracted with EtOAc. The organic extract
was washed with brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to give the crude material as
an orange oil. This material was purified by flash column
chromatography eluting with a gradient of 0% to 4% EtOAc in
petroleum ether to provide
2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
(1.7 g, 4.5 mmol, 58% yield) as alight-yellow solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 7.18 (t, J=8.2 Hz, 1H), 7.08
(d, J=8.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.4, 2.4 Hz,
1H), 6.28 (d, J=7.9 Hz, 1H), 6.11-6.21 (m, 2H), 4.27 (d, J=6.0 Hz,
2H), 3.83 (s, 3H), 3.73 (s, 3H), 3.03-3.11 (m, 4H), 1.49 (t, J=5.3
Hz, 4H), 0.33 (s, 4H). m/z (ESI): 378.2 (M+H).sup.+.
[0384] Step 3: To a solution of
2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
(1.7 g, 4.50 mmol) in DCM (20 mL) was dropwise added TFA (1.74 mL,
22.52 mmol) at 0.degree. C. and stirred at rt for 16 h. Then the
reaction mixture was evaporated to dryness, diluted with water,
neutralized with a satd. NaHCO.sub.3 solution, and extracted with
DCM. The organic layer was separated, dried over Na.sub.2SO.sub.4,
filtered, and evaporated to give
2-amino-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile as an orange semi
solid which was used for the next step without any purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 7.15 (t, J=8.1 Hz,
1H), 6.37 (dd, J=8.4, 0.9 Hz, 1H), 6.22 (dd, J=8.0, 0.9 Hz, 1H),
5.85 (s, 2H), 3.22-3.30 (m, 4H), 1.47-1.54 (m, 4H), 0.36 (s, 4H).
m/z (ESI): 228.1 (M+H).sup.+.
Intermediate 12:
7-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2-
.5]octan-6-yl)quinazolin-4-amine
##STR00066##
[0386] To a solution of ethyl
(E)-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate
(0.2 g, 0.55 mmol, Intermediate 9) in acetic acid (1.9 mL) was
added 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (0.125 g, 0.55
mmol, Intermediate 1) at rt and then was stirred at 125.degree. C.
for 1 h. The reaction mixture was diluted with water and extracted
with EtOAc (2.times.). The combined organic extracts were washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated
under vacuum. The crude product was purified through flash column
chromatography eluting with 20% EtOAc in petroleum ether to provide
7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2-
.5]octan-6-yl)quinazolin-4-amine as a yellow solid (54 mg, 18%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 12.73 (s,
1H), 8.55 (s, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H),
7.42 (s, 1H), 7.15 (t, J=2.0 Hz, 1H), 6.66 (s, 1H), 3.35-3.43 (m,
4H), 2.98 (td, J=11.8, 2.5 Hz, 2H), 2.52 (s, 3H), 2.23 (d, J=9.5
Hz, 2H), 2.03-2.14 (m, 6H), 1.93-2.05 (m, 2H), 0.35-0.48 (m, 4H).
m/z (ESI): 542.1/544.1 (M+H).sup.+.
TABLE-US-00003 TABLE 2 Intermediate 12-1 was prepared analogous to
preparation of Intermediate 12: LRMS: (ESI + Ex. # Chemical
Structure Name ve ion) m/z 12-1 ##STR00067## 7-Bromo-N-(3-(4,4-
difluoropiperidin-1-yl)-5- methylphenyl)-2-methyl-5-(6-
azaspiro[2.5]octan-6- yl)quinazolin-4-amine 556.1/558.1
Example 100:
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide
##STR00068##
[0388] To a solution of
7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2-
.5]octan-6-yl)quinazolin-4-amine (0.125 g, 0.230 mmol, Intermediate
12) and 2-hydroxyethane-1-sulfonamide (0.058 g, 0.461 mmol) in DMF
(2 mL) were added potassium phosphate tribasic (0.147 g, 0.691
mmol), copper(I) iodide (0.088 g, 0.461 mmol) and
(1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine (0.033 g, 0.230 mmol)
at rt and was heated at 95.degree. C. for 16 h. The reaction
mixture was filtered through a CELITE.RTM. pad and washed with
EtOAc. The combined organic extracts were washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and evaporated to get the crude
compound. The crude product was purified by preparative HPLC [Sun
fire C-18 (150.times.19) mm, 5.0 .mu.m, 0.1% TFA in
CH.sub.3CN/H.sub.2O] to afford
N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro-
[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide
2,2,2-trifluoroacetate (0.03 g, 0.04 mmol, 19% yield) as a yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 13.28 (s,
1H), 10.86 (s, 1H), 8.84 (s, 1H), 7.39-7.47 (m, 2H), 7.25 (s, 1H),
7.11 (t, J=2.1 Hz, 1H), 6.83 (s, 1H), 4.98 (s, 1H), 3.81 (t, J=6.1
Hz, 2H), 3.50 (t, J=6.1 Hz, 2H), 3.41 (t, J=5.7 Hz, 4H), 3.26 (d,
J=11.0 Hz, 2H), 2.87 (dd, J=12.8, 10.2 Hz, 2H), 2.33 (s, 3H),
1.99-2.22 (m, 6H), 1.10 (d, J=13.3 Hz, 2H), 0.42 (q, J=3.2 Hz, 4H).
m/z (ESI): 587.2 (M+H).sup.+.
TABLE-US-00004 TABLE 3 Example 100-1 was prepared analogous to
preparation of Example 100: LRMS: (ESI + Ex. # Chemical Structure
Name ve ion) m/z 100-1 ##STR00069## N-(4-((3-(4,4-
Difluoropiperidin-1-yl)-5- methylphenyl)amino)-2- methyl-5-(6-
azaspiro[2.5]octan-6- yl)quinazolin-7-yl)-2- hydroxyethane-1-
sulfonamide 601.3
Example 101:
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfonyl)-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-4-amine
##STR00070##
[0390] Step 1: To a solution of
2-amino-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile
(0.41 g, 1.34 mmol, Intermediate 10) in triethyl orthoformate (2.0
mL, 12 mmol) was added Ac.sub.2O (0.1 mL, 1.06 mmol) at rt and then
heated at 140.degree. C. for 16 h. The reaction mixture was
evaporated to dryness and ice-cold water was added. The solid
obtained was filtered and dried under suction to get the ethyl
(E)-N-(2-cyano-5-(methylsulfonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)for-
mimidate (0.41 g, 1.13 mmol, 84% yield) as a brown solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 8.21 (s, 1H), 7.28 (d,
J=1.5 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 3.29
(s, 3H), 3.28 (dd, J=6.4, 4.5 Hz, 4H), 1.53 (t, J=5.3 Hz, 4H), 1.35
(t, J=7.1 Hz, 3H), 0.37 (s, 4H). m/z (ESI): 362.1 (M+H).sup.+.
[0391] Step 2: To a solution of ethyl
(E)-N-(2-cyano-5-(methylsulfonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)for-
mimidate (0.19 g, 0.54 mmol) in AcOH (2 mL) was added
3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (0.121 g, 0.537
mmol, Intermediate 1) at rt and heated at 125.degree. C. for 1 h.
Then water was added to the reaction mixture and extracted with
EtOAc. The organic layer dried over Na.sub.2SO.sub.4, filtered, and
evaporated. The crude product was purified by preparative HPLC
[X-Select C18 (250.times.19) mm, 5 .mu.m, 0.1% TFA in
CH.sub.3CN/H.sub.2O) to get the
N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfonyl)-5-(6-
-azaspiro[2.5]octan-6-yl)quinazolin-4-amine 2,2,2-trifluoroacetate
(0.18 g, 0.27 mmol, 51% yield) as a yellow solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 13.44 (s, 1H), 8.88 (s, 1H),
8.03-8.09 (m, 2H), 7.37 (s, 1H), 7.17 (t, J=2.0 Hz, 1H), 6.80 (s,
1H), 3.39-3.43 (m, 7H), 3.25-3.32 (m, 2H), 3.10 (dd, J=12.7, 10.1
Hz, 2H), 2.34 (s, 3H), 2.18-2.28 (m, 2H), 2.07 (tt, J=14.0, 5.6 Hz,
4H), 1.11 (d, J=13.3 Hz, 2H), 0.44-0.42 (m, 4H). m/z (ESI): 542.2
(M+H).sup.+.
TABLE-US-00005 TABLE 4 Example 101-1 was prepared analogous to
preparation of Example 101: Ex. # Chemical Structure Name LRMS:
(ESI + ve ion) m/z 101-1 ##STR00071##
N-(3-(4,4-Difluoropiperidin-1- yl)-5-methylphenyl)-5-(6-
azaspiro[2.5]octan-6- yl)quinazolin-4-amine 464.2
Examples 102-1 and 102-2:
(R)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone
(Example 102-1) and
(S)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone
(Example 102-2)
##STR00072##
[0393] Step 1: To a solution of 1,2-dicyclopropyldisulfane (2.0 g,
13.7 mmol) in Et.sub.2O (20 mL) was dropwise added LiAlH.sub.4 (4.0
M in Et.sub.2O, 3.42 mL, 13.67 mmol) at 0.degree. C. under a
nitrogen atmosphere and stirred for 1 h at 0.degree. C. The
reaction mixture was diluted with Et.sub.2O and quenched with a
satd. aq. NH.sub.4Cl solution and extracted with Et.sub.2O
(2.times.). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give the
crude cyclopropanethiol (0.44 g, 5.90 mmol) as a colorless liquid
which was used for the next reaction. To a solution of
7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2-
.5]octan-6-yl)quinazolin-4-amine (0.32 g, 0.59 mmol, Intermediate
12) and DIPEA (0.41 mL, 2.36 mmol) in dioxane (3.2 mL) were added
xantphos (0.068 g, 0.118 mmol), Pd.sub.2(dba).sub.3 (0.054 g, 0.059
mmol) and cyclopropanethiol (0.437 g, 5.90 mmol) and the resulting
mixture was heated at 90.degree. C. for 16 h. The reaction mixture
was diluted with EtOAc, passed through a CELITE.RTM. bed, and
washed with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
purified by flash column chromatography using a gradient of 20%
EtOAc in petroleum ether to get the
7-(cyclopropylthio)-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-
-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.30 g, 0.56
mmol, 95% yield) as a light brown solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 12.74 (s, 1H), 8.50 (s, 1H), 7.53 (d,
J=1.8 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.15 (s, 1H),
6.63 (s, 1H), 3.39 (t, J=5.7 Hz, 4H), 3.30 (d, J=10.0 Hz, 2H), 3.17
(d, J=11.0 Hz, 2H), 2.20-2.33 (m, 5H), 2.07 (tt, J=14.0, 5.5 Hz,
4H), 1.16-1.29 (m, 2H), 1.06 (t, J=11.4 Hz, 2H), 0.78-0.89 (m, 1H),
0.67 (dt, J=6.7, 4.4 Hz, 2H), 0.35-0.47 (m, 4H). m/z (ESI): 536.2
(M+H).sup.+.
[0394] Step 2: To a solution of
7-(cyclopropylthio)-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(-
6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.27 g, 0.50 mmol) in
MeOH (2.7 mL) were added phenyl-13-iodanediyl diacetate (0.49 g,
1.51 mmol) and ammonium carbonate (0.29 g, 3.02 mmol) at rt and
stirred for 4 h. The reaction mixture was evaporated, diluted with
water, and extracted in EtOAc. The combined organic extracts were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to get crude product as black sticky oil. This
material was purified by flash column chromatography eluting with
60% to 70% EtOAc in petroleum ether to provide
cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)ami-
no)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone
(0.08 g, 0.14 mmol, 28% yield) as a yellow solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 12.87 (s, 1H), 8.65 (s, 1H), 7.99
(d, J=1.8 Hz, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.45 (s, 1H), 7.18 (t,
J=2.1 Hz, 1H), 6.68 (s, 1H), 4.61 (s, 1H), 3.41-3.40 (s, 4H), 3.25
(d, J=11.0 Hz, 2H), 3.00 (t, J=11.4 Hz, 2H), 2.89 (m, 1H), 2.54 (s,
3H), 2.43-2.48 (m, 2H), 2.08 (td, J=13.9, 7.0 Hz, 4H), 0.96-1.13
(m, 2H), 0.91-1.00 (m, 2H), 0.44 (s, 4H). m/z (ESI): 567.3
(M+H).sup.+. The racemic mixture was separated via chiral
preparative SFC using a Chiralpak AD (250.times.21 mm, 5 mm) column
with a mobile phase of 50% liquid CO.sub.2 and 50% IPA to give mg
of
(R)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amin-
o)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone
(peak 1, Example 102-1). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 12.87 (s, 1H), 8.65 (s, 1H), 7.99 (d, J=1.8 Hz, 1H),
7.87 (d, J=1.8 Hz, 1H), 7.45 (s, 1H), 7.18 (t, J=2.1 Hz, 1H), 6.68
(s, 1H), 4.61 (s, 1H), 3.41-3.40 (s, 4H), 3.25 (d, J=11.0 Hz, 2H),
3.00 (t, J=11.4 Hz, 2H), 2.89 (m, 1H), 2.54 (s, 3H), 2.43-2.48 (m,
2H), 2.08 (td, J=13.9, 7.0 Hz, 4H), 0.96-1.13 (m, 2H), 0.91-1.00
(m, 2H), 0.44 (s, 4H). m/z (ESI): 567.3 (M+H).sup.+ and 24 mg of
(S)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)--
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone
(peak 2, Example 102-2), .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 12.87 (s, 1H), 8.65 (s, 1H), 7.99 (d, J=1.8 Hz, 1H),
7.87 (d, J=1.8 Hz, 1H), 7.44 (s, 1H), 7.17 (t, J=2.1 Hz, 1H), 6.68
(s, 1H), 4.61 (s, 1H), 3.43-3.40 (s, 4H), 3.26 (d, J=11.0 Hz, 2H),
3.00 (t, J=11.4 Hz, 2H), 2.85 (m, 1H), 2.55 (s, 3H), 2.41-2.48 (m,
2H), 2.08 (td, J=13.9, 7.0 Hz, 4H), 0.96-1.13 (m, 2H), 0.91-1.00
(m, 4H), 0.44 (s, 4H). m/z (ESI): 567.3 (M+H).sup.+.
[0395] The stereochemistry of Examples 102-1 and 102-2 was assigned
arbitrarily.
Example 103:
2-Hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide)
##STR00073##
[0397] Step 1: To a solution of ethyl
1-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate
(0.35 g, 0.97 mmol, Intermediate 9) and
3-methyl-5-(3,3,3-trifluoropropoxy)aniline (0.21 g, 0.97 mmol,
Intermediate 2) in AcOH (2 mL, 35 mmol) was heated at 100.degree.
C. for 2 h. Then the reaction mixture was concentrated under
reduced pressure and the residue was dissolved in EtOAc. The
organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The crude
material was purified by flash column chromatography eluting with a
gradient of 30% to 35% EtOAc in petroleum ether to provide
7-bromo-N-(3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)-5-(6-azaspiro[2.5]o-
ctan-6-yl)quinazolin-4-amine (220 mg, 31% yield). m/z (ESI): 535.1
(M)+.
[0398] Step 2: To a solution of
7-bromo-N-(3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)-5-(6-azaspiro[2.5]o-
ctan-6-yl)quinazolin-4-amine (0.220 g, 0.411 mmol) and
2-hydroxyethane-1-sulfonamide (0.062 g, 0.493 mmol) in DMF (4 mL)
were added tripotassium phosphate (0.174 g, 0.822 mmol) and copper
(I) iodide (0.078 g, 0.411 mmol), followed by
(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.029 g, 0.205 mmol)
at rt and the reaction mixture was heated at 100.degree. C. for 16
h. The reaction mixture passed through a bed of CELITE.RTM. and
washed with EtOAc. The organic layer was washed with water, brine,
dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness.
The crude product was purified by reverse-phase preparative HPLC
(C-18 gold column, CH.sub.3CN/H.sub.2O, gradient 65% to 70%) to
provide
2-hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide (0.040
g, 0.069 mmol, 17% yield) as an off-white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 10.78 (s, 1H), 8.79 (s, 1H),
7.35-7.45 (m, 2H), 7.31 (t, J=2.2 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H),
6.76 (s, 1H), 5.02 (s, 1H), 4.24 (t, J=5.9 Hz, 2H), 3.80 (t, J=6.2
Hz, 2H), 3.21-3.25 (m, 5H), 2.84 (m, 4H), 2.36 (s, 3H), 2.16 (t,
J=12.0 Hz, 2H), 1.09 (d, J=13.3 Hz, 2H), 0.43 (m, 4H). m/z (ESI):
580.2 (M+H).sup.+.
TABLE-US-00006 TABLE 5 Examples 103-1 and 103-2 were prepared
analogous to preparation of Example 103: LRMS: (ESI + Ex. #
Chemical Structure Name ve ion) m/z 103-1 ##STR00074## N-(4-((3,5-
Dimethylphenyl)amino)- 5-(6-azaspiro[2.5]octan-
6-yl)quinazolin-7-yl)-2- hydroxyethane-1- sulfonamide 482.2 103-2
##STR00075## N-(5-(6- Azaspiro[2.5]octan-6- yl)-4-((3-(3,3,3-
trifluoropropoxy)phenyl) amino)quinazolin-7-yl)- 2-hydroxyethane-1-
sulfonamide 566.1
Example 104:
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6--
azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide
##STR00076##
[0400] Step 1: A solution of ethyl
(E)-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate
(0.50 g, 1.38 mmol, Intermediate 9) and
2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (0.31 g,
1.38 mmol, Intermediate 4) in AcOH (2 mL) was heated at 125.degree.
C. for 45 min. The reaction mixture was diluted with water and
extracted with EtOAc. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The crude material was purified by flash column chromatography
eluting with 0% to 30% EtOAc in petroleum ether to provide
7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-4-amine (0.15 g, 0.28 mmol, 20%
yield) as a pale-yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 13.67 (s, 1H), 8.76 (s, 1H), 7.89-7.88 (m, 2H), 7.76
(s, 1H), 3.95 (t, J=5.8 Hz, 4H), 3.19 (d, J=11.1 Hz, 2H), 3.05 (q,
J=12.2, 11.3 Hz, 2H), 2.36 (s, 3H), 1.96-2.05 (m, 4H), 1.14-1.26
(m, 4H), 0.38 (s, 4H). m/z (ESI): 544.2/546.2 (M+H).sup.+.
[0401] Step 2: A mixture of
7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-4-amine (0.14 g, 0.26 mmol),
2-hydroxyethane-1-sulfonamide (0.048 g, 0.386 mmol), potassium
phosphate tribasic (0.164 g, 0.771 mmol), copper(I) iodide (0.098
g, 0.514 mmol) and (1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine
(0.037 g, 0.257 mmol) in DMF (2 mL) was heated at 90.degree. C. for
16 h. The reaction mixture was filtered through a CELITE.RTM. pad
and washed with EtOAc. The organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness.
The crude product was purified by preparative HPLC [Kinetex Evo
C-18 (250.times.30) mm, 5 .mu.m, 0.1% TFA, CH.sub.3CN/H.sub.2O] to
afford
N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6--
azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide
2,2,2-trifluoroacetate (0.07 g, 0.10 mmol, 39% yield) as a pale
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
13.86 (s, 1H), 10.74 (s, 1H), 8.90 (s, 1H), 7.86 (s, 1H), 7.46 (s,
2H), 3.95 (t, J=5.8 Hz, 4H), 3.80 (t, J=6.2 Hz, 2H), 3.48 (d,
J=12.4 Hz, 2H), 3.22 (d, J=10.8 Hz, 2H), 2.88 (t, J=11.5 Hz, 2H),
2.43-2.48 (m, 2H), 2.38 (s, 3H), 2.02 (m, 4H), 1.03 (d, J=12.9 Hz,
2H), 0.40-0.46 (m, 4H). m/z (ESI): 589.2 (M+H).sup.+.
Example 105:
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide
##STR00077##
[0403] Step 1: A mixture of formic acid (5 mL) and sulfuric acid
(0.2 mL, 3.75 mmol) was heated at 100.degree. C. for 5 min. A
solution of
2-amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.6 g,
5.2 mmol, Intermediate 8) in formic acid (5 mL) was added dropwise
to the above mixture for 5 min at the same temperature and heating
was continued for 16 h. The reaction mixture was treated with ice
and neutralized with an aq. satd. NaHCO.sub.3 solution and
extracted with EtOAc (2.times.). The combined organic extracts were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The residue was triturated
with Et.sub.2O to provide
7-bromo-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4(3H)-one (1.6 g,
4.8 mmol, 92% yield) as a light-yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 11.96 (s, 1H), 7.99 (s, 1H), 7.27 (d,
J=1.9 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 3.04 (s, 4H), 1.53 (s, 4H),
0.32 (s, 4H). m/z (ESI): 334.1/336.1 (M+H).sup.+.
[0404] Step 2: A solution of
7-bromo-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4(3H)-one (0.35 g,
1.05 mmol) in toluene (7 mL) was treated with phosphorus
oxychloride (0.195 mL, 2.094 mmol) and N,N-diethylaniline (0.313 g,
2.094 mmol) at rt and was heated at 120.degree. C. for 2 h. It was
cooled to rt, volatiles were evaporated under reduced pressure to
get crude residue which was further co-distilled with toluene to
afford 7-bromo-4-chloro-5-(6-azaspiro[2.5]octan-6-yl)quinazoline as
a brown solid (0.43 g). It was directly used for the next step
without further purification. m/z (ESI): 352.1/354.1
(M+H).sup.+.
[0405] Step 3: A glass microwave vial was successively charged with
7-bromo-4-chloro-5-(6-azaspiro[2.5]octan-6-yl)quinazoline (0.21 g,
0.57 mmol), 2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-amine
(0.16 g, 0.68 mmol, Intermediate 5) and DIPEA (0.099 mL, 0.567
mmol) in NMP (6 mL) and was subjected to microwave irradiation at
150.degree. C. for 4 h. The reaction mixture was quenched with
water and extracted with EtOAc (2.times.). The combined organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The crude material was
absorbed onto a plug of silica gel and purified by flash column
chromatography eluting with a gradient of 0% to 30% EtOAc in
petroleum ether to provide
7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-5-(6-azas-
piro[2.5]octan-6-yl)quinazolin-4-amine (0.045 g, 0.083 mmol, 15%
yield) as a pale-yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 12.92 (s, 1H), 8.68 (s, 1H), 7.83 (d, J=2.0 Hz, 1H),
7.71 (d, J=1.9 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.18 (s, 1H), 3.70
(s, 4H), 2.99 (t, J=12.0 Hz, 2H), 2.56 (q, J=1.9 Hz, 2H), 2.43-2.48
(m, 2H), 2.27 (s, 3H), 2.02-2.04 (s, 4H), 0.85 (s, 2H), 0.42 (d,
J=8.9 Hz, 4H). m/z (ESI): 543.1/545.1 (M+H).sup.+.
[0406] Step 4: A solution of
7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-5-(6-azas-
piro[2.5]octan-6-yl)quinazolin-4-amine (0.04 g, 0.07 mmol),
2-hydroxyethane-1-sulfonamide (0.014 g, 0.110 mmol), potassium
phosphate tribasic (0.047 g, 0.221 mmol), copper(I) iodide (0.028
g, 0.147 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (10
mg, 0.074 mmol) in DMF (2 mL) was heated at 95.degree. C. for 16 h.
The reaction mixture was filtered through a CELITE.RTM. pad and
washed with EtOAc. The combined organic extracts were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated under
vacuum. The crude product was purified by preparative HPLC [Kinetex
EVO C18 (250.times.21.2) mm, 5 .mu.m, 0.1% TFA CH.sub.3CN/H.sub.2O]
to afford
N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)-5-(6-az-
aspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide
2,2,2-trifluoroacetate (0.014 g, 0.020 mmol, 27% yield) as a yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 13.23 (s,
1H), 10.70 (s, 1H), 8.83 (s, 1H), 7.45 (q, J=2.1 Hz, 3H), 7.27 (s,
1H), 3.69-3.84 (m, 6H), 3.47 (t, J=6.2 Hz, 2H), 3.23 (d, J=10.9 Hz,
2H), 2.86 (t, J=11.5 Hz, 2H), 2.46 (dq, J=3.7, 2.1 Hz, 2H), 2.23
(t, J=11.9 Hz, 2H), 2.12-2.18 (m, 6H), 1.09 (d, J=13.3 Hz, 2H),
0.39-0.48 (m, 4H). m/z (ESI): 588.3 (M+H).sup.+.
TABLE-US-00007 TABLE 6 Examples 105-1 and 105-2 were prepared
analogous to preparation of Example 105: LRMS: (ESI + Ex. #
Chemical Structure Name ve ion) m/z 105-1 ##STR00078##
N-(4-((6-(4,4- Difluoropiperidin-1-yl)-4-
methylpyridin-2-yl)amino)-5- (6-azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)-2- hydroxyethane-1-sulfonamide 588.3 105-2
##STR00079## N-(4-(3-(4,4-Difluoropiperidin-
1-yl)-5-methylphenoxy)-5-(6- azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)-2- hydroxyethane-1-sulfonamide 588.2
Example 106:
N-(1-((3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro-
[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide
##STR00080## ##STR00081##
[0408] Step 1: To a solution of
4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (4 g, 12.9 mmol)
in DCM (100 mL) were added oxalyl chloride (2.26 mL, 25.8 mmol)
dropwise at 0.degree. C. followed by DMF (0.20 mL, 2.58 mmol). The
reaction mixture was stirred at rt for 1 h. The reaction mixture
was evaporated under reduced pressure and was co-distilled with
toluene to afford crude
4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (4.2 g, 12.8
mmol, 99% yield) as a yellow solid. This was taken to the next step
without further purification.
[0409] Step 2: To a solution of diethylamine (1.87 g, 25.6 mmol) in
dioxane (100 mL) was added Et.sub.3N (7.13 mL, 51.1 mmol) followed
by 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (4.2 g,
12.8 mmol) at 0.degree. C. The reaction mixture was stirred at rt
for 16 h before it was quenched with cold water and extracted with
EtOAc. The organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to afford 4-bromo-N,
N-diethyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.5 g, 12.3 mmol,
96% yield) as a light brown syrup. It was taken to the next step
without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 7.21 (d, J=7.7 Hz, 2H), 7.03-7.08 (m, 1H), 3.55 (s,
3H), 3.07-3.22 (m, 3H), 2.82 (ddd, J=11.0, 7.0, 3.6 Hz, 2H),
1.32-1.48 (m, 4H), 1.17 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.1 Hz, 3H),
0.31 (d, J=1.9 Hz, 4H).
[0410] Step 3: A solution of 2,2,6,6-tetramethylpiperidine (0.97 g,
6.84 mmol) in THF (20 mL) was cooled to -78.degree. C. and treated
with n-BuLi (2.5 M solution in hexanes, 2.74 mL, 6.84 mmol). The
reaction mixture was stirred at the same temperature for 30 min and
then a solution of 4-bromo-N,
N-diethyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.0 g, 2.7 mmol)
in THF (10 mL) was dropwise added to it. The resulting brown
solution was stirred at the same temperature for 45 minutes and
then DMF (1.06 mL, 13.69 mmol) was added dropwise to it at the same
temperature. The reaction mixture was stirred for 1 h and quenched
with an aq. satd. NH.sub.4Cl solution. The aqueous layer was
extracted with EtOAc, washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford
4-bromo-N,
N-diethyl-2-formyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (1.1 g
crude) as a light brown gum. The crude product was taken for next
step without further purification. m/z (ESI): 393.1/395.1
(M+H).sup.+.
[0411] Step 4: To a solution of 4-bromo-N,
N-diethyl-2-formyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (3.4 g,
8.6 mmol) in AcOH (12 mL) was added hydrazine hydrate (0.86 g,
17.29 mmol) at rt and heated to 110.degree. C. for 24 h. The
reaction mixture was quenched with water and extracted with EtOAc.
The organic layer was washed with 10% NaHCO.sub.3 solution, brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography using 20% EtOAc in petroleum ether to afford
6-bromo-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-1(2H)-one (0.5 g,
1.5 mmol, 17% yield) as a pale-yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 12.29 (s, 1H), 8.11 (s, 1H), 7.32 (d,
J=1.9 Hz, 2H), 3.10-3.20 (m, 4H), 1.55 (br s, 4H), 0.34 (s, 4H).
m/z (ESI): 334.1/336.1 (M)+.
[0412] Step 5: To solution of
6-bromo-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-1(2H)-one (0.4 g,
1.2 mmol) in toluene (8 mL) were added phosphorus oxychloride
(0.223 mL, 2.394 mmol) and N,N-diethylaniline (0.357 g, 2.394 mmol)
at rt. The resulting mixture was heated at 120.degree. C. for 2 h
before it was evaporated under reduced pressure and the residue was
co-distilled with toluene to afford
6-bromo-1-chloro-8-(6-azaspiro[2.5]octan-6-yl)phthalazine as a
brown solid (0.6 g). The crude material taken for next step without
further purification.
[0413] Step 6: A mixture of
6-bromo-1-chloro-8-(6-azaspiro[2.5]octan-6-yl)phthalazine (0.30 g,
0.85 mmol) and 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline
(0.385 g, 1.701 mmol) in tert-butanol (2.5 mL) was heated for
90.degree. C. for 16 h. The reaction mixture was concentrated under
reduced pressure and purified by preparative HPLC purification
[Kinetex EVO C-18 (250.times.21.2) mm, 5 .mu.m, 0.1% TFA in
CH.sub.3CN/H.sub.2O] to afford
6-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-8-(6-azaspiro[2-
.5]octan-6-yl)phthalazin-1-amine (0.06 g, 0.11 mmol, 13% yield) as
a light brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
ppm 13.34 (s, 1H), 8.99 (s, 1H), 8.34 (q, J=1.9 Hz, 2H), 7.05 (s,
1H), 6.93 (s, 1H), 6.89 (s, 1H), 3.43 (t, J=5.7 Hz, 4H), 3.27 (d,
J=11.4 Hz, 2H), 3.10 (t, J=11.4 Hz, 2H), 2.34 (s, 3H), 2.08-2.15
(m, 6H), 1.07 (d, J=13.5 Hz, 2H), 0.40 (s, 4H). m/z (ESI):
542.1/544.1 (M)+.
[0414] Step 7: A mixture of
6-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-8-(6-azaspiro[2-
.5]octan-6-yl)phthalazin-1-amine (0.06 g, 0.111 mmol),
2-hydroxyethane-1-sulfonamide (0.021 g, 0.166 mmol), potassium
phosphate tribasic (0.047 g, 0.221 mmol), copper(I) iodide (0.021
g, 0.111 mmol) and (1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine (8
mg, 0.055 mmol) in DMF (2 mL) was heated at 95.degree. C. for 16 h.
The reaction mixture was filtered through a CELITE.RTM. bed and
washed with EtOAc. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was purified by preparative HPLC
[Kinetex EVO C-18 (250.times.21.2) mm, 5 .mu.m, 0.1% TFA in
CH.sub.3CN/H.sub.2O] to afford
N-(1-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro-
[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 12.97
(s, 1H), 10.93 (s, 1H), 9.05 (s, 1H), 7.72-7.78 (m, 2H), 7.03 (t,
J=2.1 Hz, 1H), 6.89 (d, J=14.3 Hz, 2H), 3.82 (t, J=6.1 Hz, 3H),
3.55 (t, J=6.1 Hz, 2H), 3.43 (d, J=11.5 Hz, 4H), 3.31 (d, J=11.1
Hz, 2H), 2.84-2.95 (m, 2H), 2.34 (s, 3H), 1.99-2.12 (m, 6H), 1.09
(d, J=13.2 Hz, 2H), 0.36-0.46 (m, 4H). m/z (ESI): 587.2
(M+H).sup.+.
Additional Examples
[0415] The following Examples 107-140 can be made according to the
procedure similar to the above examples by using starting
commercially available materials or can be made according to
procedure familiar to those skilled in the art.
TABLE-US-00008 Ex. # Chemical Structure Name 107 ##STR00082##
(R)-2-Hydroxy-N-(4-((3-methyl-5-(2-
methylmorpholino)phenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7- yl)ethane-1-sulfonamide 108
##STR00083## (R)-2-Hydroxy-N-(4-((4-methyl-6-(2-
methylmorpholino)pyridin-2-yl)amino)-
5-(6-azaspiro[2.5]octan-6-yl)quinazolin- 7-yl)ethane-1-sulfonamide
109 ##STR00084## (R)-2-Hydroxy-N-(4-((6-methyl-2-(2-
methylmorpholino)pyrimidin-4-yl)
amino)-5-(6-azaspiro[2.5]octan-6-yl)
quinazolin-7-yl)ethane-1-sulfonamide 110 ##STR00085##
2-Hydroxy-N-(4-((2-((1-hydroxy-2- methylpropan-2-yl)amino)-6-
methylpyrimidin-4-yl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7- yl)ethane-1-sulfonamide 111
##STR00086## N-(4-((2-Fluoro-3-((1-hydroxy-2-
methylpropan-2-yl)amino)phenyl) amino)-5-(6-azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)-2- hydroxyethane-1-sulfonamide 112 ##STR00087##
2-Hydroxy-N-(4-((3-(2-hydroxy-2- methylpropoxy)phenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7- yl)ethane-1-sulfonamide 113
##STR00088## 4-((2-(4,4-Difluoropiperidin-1-yl)-6-
methylpyrimidin-4-yl)amino)-N-(3-
methyloxetan-3-yl)-5-(6-azaspiro[2.5]
octan-6-yl)quinazoline-7-sulfonamide 114 ##STR00089##
(S)-N-(4-((6-(4,4-Difluoropiperidin-1-yl)-
4-methylpyridin-2-yl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-
1-hydroxypropane-2-sulfonamide 115 ##STR00090##
(R)-N-(4-((6-(4,4-Difluoropiperidin-1-yl)-
4-methylpyridin-2-yl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-
1-hydroxypropane-2-sulfonamide 116 ##STR00091##
N-(4-((2-(3,3-Difluoroazetidin-1-yl)-6-
methylpyrimidin-4-yl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7-
yl)-2-hydroxyethane-1-sulfonamide 117 ##STR00092##
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-
methylpyrimidin-4-yl)amino)-8-fluoro-
5-(6-azaspiro[2.5]octan-6-yl)quinazolin-
7-yl)-2-hydroxyethane-1-sulfonamide 118 ##STR00093##
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-
6-methylpyrimidin-4-yl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)pyrido[4,3-
d]pyrimidin-7-yl)-2-hydroxyethane-1- sulfonamide 119 ##STR00094##
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-
methylpyrimidin-4-yl)amino)-5-(7-
azaspiro[3.5]nonan-7-yl)quinazolin-7-
yl)-2-hydroxyethane-1-sulfonamide 120 ##STR00095##
N-(4-((2-(4,4-Difluoropiperidin-1- yl)pyrimidin-4-yl)amino)-5-(4,4-
dimethylazepan-1-yl)quinazolin-7-yl)-2- hydroxyethane-1-sulfonamide
121 ##STR00096## 2-((4-((2-(4,4-Difluoropiperidin-1-yl)-
6-methylpyrimidin-4-yl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7- yl)sulfonyl)ethan-1-ol 122
##STR00097## N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5-
methylphenyl)thio)-5-(6-azaspiro[2.5]
octan-6-yl)quinazolin-7-yl)-2-hydroxy- ethane-1-sulfonamide 123
##STR00098## 7-(Azetidin-3-ylsulfonyl)-N-(2-(4,4-
difluoropiperidin-1-yl)-6-methyl-
pyrimidin-4-yl)-5-(6-azaspiro[2.5] octan-6-yl)quinazolin-4-amine
124 ##STR00099## N-(tert-Butyl)-3-((7-((2-
hydroxyethyl)sulfonamido)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-4- yl)amino)benzenesulfonamide
125 ##STR00100## N-(4-((3-(Cyclopentylsulfonyl)-4-
methylphenyl)amino)-5-(6- azaspiro[2.5]octan-6-yl)quinazolin-
7-yl)-2-hydroxyethane-1-sulfonamide 126 ##STR00101##
N-(tert-Butyl)-4-((6-(N-(tert- butyl)sulfamoyl)pyridin-2-yl)amino)-
5-(6-azaspiro[2.5]octan-6-yl) quinazoline-7-sulfonamide 127
##STR00102## N-(tert-Butyl)-4-(chroman-5-ylamino)-
5-(6-azaspiro[2.5]octan-6-yl) quinazoline-7-sulfonamide 128
##STR00103## N-(1-((6-(4,4-Difluoropiperidin-1-
yl)-4-methylpyridin-2-yl)amino)-8-(6-
azaspiro[2.5]octan-6-yl)phthalazin-6-
yl)-2-hydroxyethane-1-sulfonamide 129 ##STR00104##
N-(1-((6-(4,4-Difluoropiperidin-1-yl)-
4-methylpyridin-2-yl)amino)-8-(6-
azaspiro[2.5]octan-6-yl)isoquinolin-6-
yl)-2-hydroxyethane-1-sulfonamide 130 ##STR00105##
N-(1-((3-(4,4-Difluoropiperidin-1-yl)- 5-methylphenyl)amino)-8-(6-
azaspiro[2.5]octan-6-yl)isoquinolin-
6-yl)-2-hydroxyethane-1-sulfonamide 131 ##STR00106##
2-(4-((3-(4,4-Difluoropiperidin-1-yl)-5- methylphenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-7- yl)isothiazolidine
1,1-dioxide 132 ##STR00107## N-(4-((3-(3,3-Difluoro-6-
azabicyclo[3.1.1]heptan-6-yl)-5- methylphenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-
7-yl)-2-hydroxyethane-1-sulfonamide 133 ##STR00108##
N-(4-((3-(6,6-Difluoro-3- azabicyclo[3.1.1]heptan-3-yl)-5-
methylphenyl)amino)-5-(6- azaspiro[2.5]octan-6-yl)quinazolin-
7-yl)-2-hydroxyethane-1-sulfonamide 134 ##STR00109##
N-(4-((3-(4,4-Difluoropiperidin-1- yl)-4-methylphenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin-
7-yl)-2-hydroxyethane-1-sulfonamide 135 ##STR00110##
4-((3-(4,4-Difluoropiperidin-1-yl)-5- methylphenyl)amino)-N-(2-
hydroxyethyl)-5-(6-azaspiro[2.5]
octan-6-yl)quinazoline-7-carboxamide 136 ##STR00111##
2-((8-((3-(4,4-Difluoropiperidin-1- yl)-5-methylphenyl)amino)-1-(6-
azaspiro[2.5]octan-6-yl)-2,7- naphthyridin-3-yl)amino)-2-
methylpropan-1-ol 137 ##STR00112##
2-((5-((3-(4,4-Difluoropiperidin-1- yl)-5-methylphenyl)amino)-4-(6-
azaspiro[2,5]octan-6-yl)-1,6- naphthyridin-2-yl)amino)-2-
methylpropan-1-ol 138 ##STR00113##
2-((5-((3-(4,4-Difluoropiperidin-1- yl)-5-methylphenyl)amino)-4-(6-
azaspiro[2.5]octan-6-yl)pyrido[4,3- d]pyrimidin-2-yl)amino)-2-
methylpropan-1-ol 139 ##STR00114##
2-(4-((3-(4,4-Difluoropiperidin-1- yl)-5-methylphenyl)amino)-5-(6-
azaspiro[2.5]octan-6-yl)quinazolin- 7-yl)propan-2-ol 140
##STR00115## N-(3-(4,4-Difluoropiperidin-1-yl)-
5-methylphenyl)-5-(6-azaspiro[2.5]
octan-6-yl)pyrido[3,4-d]pyrimidin- 4-amine
Biological Examples
[0416] The following assays were used in testing the exemplary
compounds of the invention. Data for those examples tested in
accordance with the procedures described below are presented in
Table A below.
[0417] KIF18A Enzyme Assay: Microtubule-stimulated ATPase activity
assay is used to measure KIF18A enzyme activity after treatment
with compound. Compounds were 2-fold serially diluted in DMSO
(Sigma Inc) over 22-point concentration range. Recombinant human
KIF18A (1-467 His-tagged) protein was expressed using a baculovirus
system and purified by affinity chromatography by Amgen Inc.
Concentrations of KIF18A protein, microtubules (MT), and ATP in the
reaction were optimized for standardized homogenous enzyme assay
using ADP-Glo.TM. Kinase/ATPase Assay Kit (Promega Inc). The assay
measures ADP formed from the ATPase reaction. Prepare reaction
buffer [(15 mM Tris, pH 7.5 (Teknova Inc), 10 mM MgCl2 (IT Baker
Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1 .mu.M Taxol
(Cytoskeleton Inc), and 30 .mu.g/mL pig microtubules (Cytoskeleton
Inc)]. Add compound and KIF18A protein (30 nM) to prepared reaction
buffer and incubated for 15 minutes at room temperature, next add
ATP (at Kin, 75 .mu.M) to the reaction mixture and incubated for an
additional 15 minutes at room temperature. Mix 5 .mu.l of
ADP-Glor.TM. Reagent and 2.5 .mu.l of the reaction mixture and
incubate for 40 minutes at room temperature. Add 10 .mu.l ADP-Glorh
Detection Reagent and incubate for 40 minutes at room temperature.
Read luminescence using EnVision microplate reader with
ultra-luminescence module (Perkin Elmer Inc).
Concentration-response curve-fitting and IC.sub.50 determination
was performed using Genedata Screener Software (Standard 15.0.1,
Genedata Inc) with a four-parameter logistic regression fit
model.
[0418] Table A provides data for compounds exemplified in the
present application and priority document thereof, as
representative compounds of the present invention, as follows:
chemical name (as named by either ACD software or ChemDraw
(Professional 15.0)) and biological data (IC.sub.50 in .mu.M). Ex.
# refers to Example No.
TABLE-US-00009 TABLE A BIOLOGICAL DATA KIF18A ATPase IC.sub.50 Ex.
# Compound Name (.mu.M) 100
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5- 0.049
methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide 100-1
N-(4-((3-(4,4-Difluoropiperidin-1-yl)-5- 0.955
methylphenyl)amino)-2-methyl-5-(6-azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide 101
N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-7- 0.940
(methylsulfonyl)-5-(6-azaspiro[2.5]octan-6-yl)quina- zolin-4-amine
101-1 N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-5-(6- 3.340
azaspiro[2.5]octan-6-yl)quinazolin-4-amine 102-1
(R)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5- 0.073
methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)(imino)-l6-sulfanone 102-2
(S)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5- 0.262
methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-
yl)quinazolin-7-yl)(imino)-l6-sulfanone 103
2-Hydroxy-N-(4-((3-methyl-5-(3,3,3- 0.175
trifluoropropoxy)phenyl)amino)-5-(6-azaspi-
ro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide 103-1
N-(4-((3,5-Dimethylphenyl)amino)-5-(6-azaspi- 0.403
ro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxy- ethane-1-sulfonamide
103-2 N-(5-(6-Azaspiro[2.5]octan-6-yl)-4-((3-(3,3,3- 0.061
trifluoropropoxy)phenyl)amino)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 104
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyri- 0.129
midin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quina-
zolin-7-yl)-2-hydroxyethane-1-sulfonamide 105
N-(4-((2-(4,4-Difluoropiperidin-1-yl)-6-methylpyridin-4- 0.082
yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 105-1
N-(4-((6-(4,4-Difluoropiperidin-1-yl)-4-methylpyridin-2- 0.078
yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-
hydroxyethane-1-sulfonamide 105-2
N-(4-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphe- 2.84
noxy)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hy-
droxyethane-1-sulfonamide 106
N-(1-((3-(4,4-Difluoropiperidin-1-yl)-5- 0.025
methylphenyl)amino)-8-(6-azaspiro[2.5]octan-6-
yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide
[0419] The foregoing invention has been described in some detail by
way of illustration and example, for purposes of clarity and
understanding. Those skilled in the art understand that changes and
modifications may be practiced within the scope of the appended
claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0420] All patents, patent applications and publications cited
herein are hereby incorporated by reference in their entirety for
all purposes to the same extent as if each individual patent,
patent application or publication were so individually denoted.
* * * * *
References